article dict | reports listlengths 1 3.97k |
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{
"abstract": "The intravitreal dexamethasone implant is a sustained-release anti-inflammatory drug system that releases 0.7 mg of dexamethasone into the vitreous cavity. The following case report describes a rare complication: accidental injection of the dexamethasone implant into the crystalline lens. A 73-year-old woman was diagnosed with central retina vein occlusion and cystoid macular edema. Initial tSreatment included three monthly intravitreal doses of anti-vascular endothelial growth factor treatment, which was not successful. Treatment was then modified to an intravitreal dexamethasone implant. Ten weeks later, the implant was observed in the posterior cortex of the crystalline lens. Because no improvement had occurred, the patient underwent phacoemulsification surgery, during which part of the lens migrated into the vitreous cavity. Therefore, 23-gauge pars plana complete vitrectomy was performed with trans-surgical administration of intravitreal aflibercept. Crystalline lens injury due to an intravitreal dexamethasone implant is a rare complication and typically results from the injection procedure. Immediate surgical or conservative approaches should be considered on an individual basis.",
"affiliations": "Retina Department, Asociación para Evitar la Ceguera en México, Hospital Dr. Luis Sanchez Bulnes, Mexico City, Mexico.;Retina Department, Asociación para Evitar la Ceguera en México, Hospital Dr. Luis Sanchez Bulnes, Mexico City, Mexico.;Cataract Department, Asociación para Evitar la Ceguera en México, Hospital Dr. Luis Sanchez Bulnes, Mexico City, Mexico.;Retina Department, Asociación para Evitar la Ceguera en México, Hospital Dr. Luis Sanchez Bulnes, Mexico City, Mexico.;Retina Department, Asociación para Evitar la Ceguera en México, Hospital Dr. Luis Sanchez Bulnes, Mexico City, Mexico.",
"authors": "Cervantes|Andrés Lisker|AL|0000-0001-6133-0116;Crim|Nicolás|N|;García-Arroyo|Santiago|S|;Morales-Cantón|Virgilio|V|;Montoya|Raúl Velez|RV|",
"chemical_list": "D004343:Drug Implants; D005938:Glucocorticoids; D003907:Dexamethasone",
"country": "Brazil",
"delete": false,
"doi": "10.5935/0004-2749.20200066",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-2749",
"issue": "83(3)",
"journal": "Arquivos brasileiros de oftalmologia",
"keywords": null,
"medline_ta": "Arq Bras Oftalmol",
"mesh_terms": "D000368:Aged; D003907:Dexamethasone; D004343:Drug Implants; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D058449:Intravitreal Injections; D007908:Lens, Crystalline; D014792:Visual Acuity",
"nlm_unique_id": "0400645",
"other_id": null,
"pages": "246-249",
"pmc": null,
"pmid": "32490978",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unintentional injection of a dexamethasone implant into the crystalline lens: a case report.",
"title_normalized": "unintentional injection of a dexamethasone implant into the crystalline lens a case report"
} | [
{
"companynumb": "MX-ALLERGAN-2023758US",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nScarce data are available regarding the proportion of drugs that have provoked new-onset seizures. The aim of this study was to investigate the types of causative drugs of drug-induced new-onset seizures in a relatively large population of patients who were admitted to our epilepsy monitoring unit.\n\n\nMETHODS\nUsing a hospital-based database, patients with new-onset seizures were selected and the underlying etiology of new-onset seizures was reviewed. Based on the etiologic conditions, acute symptomatic seizure was classified into 7 groups of provocation factors: drug, alcohol, encephalitis, stroke, hypoxic injury, metabolic, and unclassified. Causative drugs for new-onset seizures were further investigated.\n\n\nRESULTS\nAltogether, 363 patients with new-onset seizures were reviewed in this study. The most common cause of new-onset seizures was epilepsy, followed by syncope, acute symptomatic seizure, and others. Drugs were found to be the most common provocation factor for acute symptomatic seizures. The most common causative drug was antihistamine, followed by stimulants, antibiotics, and other drugs. Most patients with antihistamine-induced seizures had normal renal function and were under treatment at the therapeutic dose.\n\n\nCONCLUSIONS\nIn our population, antihistamine accounted for the highest proportion of drug-induced seizures. Considering that antihistamines are widely used as over-the-counter drugs around the world, they should be considered a possible cause of new-onset seizures.",
"affiliations": "Department of Neurology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea.;Department of Neurology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea.;Department of Neurology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea. kjbin80@korea.ac.kr.",
"authors": "Kim|Hayom|H|https://orcid.org/0000-0002-9991-3664;Kim|Seong Hwan|SH|https://orcid.org/0000-0002-0778-1570;Kim|Jung Bin|JB|https://orcid.org/0000-0002-8013-9349",
"chemical_list": "D000927:Anticonvulsants; D006633:Histamine Antagonists; D002220:Carbamazepine",
"country": "Italy",
"delete": false,
"doi": "10.1007/s10072-021-05043-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-1874",
"issue": "42(6)",
"journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology",
"keywords": "Acute symptomatic seizure; Antihistamines; Drug-induced seizure; New-onset seizure",
"medline_ta": "Neurol Sci",
"mesh_terms": "D000927:Anticonvulsants; D002220:Carbamazepine; D004828:Epilepsies, Partial; D004829:Epilepsy, Generalized; D004830:Epilepsy, Tonic-Clonic; D006633:Histamine Antagonists; D006801:Humans; D012640:Seizures",
"nlm_unique_id": "100959175",
"other_id": null,
"pages": "2505-2508",
"pmc": null,
"pmid": "33438141",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Antihistamines as a common cause of new-onset seizures: a single-center observational study.",
"title_normalized": "antihistamines as a common cause of new onset seizures a single center observational study"
} | [
{
"companynumb": "KR-PERRIGO-21KR012116",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PSEUDOEPHEDRINE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is associated with worse outcomes. The combination of ledipasvir (LDV) and sofosbuvir (SOF) has been approved for HCV treatment after LT, but there are limited data on the effectiveness and safety of LDV/SOF in the \"real-world\" setting. This multicenter study is the largest report to date on the effectiveness and safety of LDV/SOF in the post-LT setting. A total of 204 patients (72% male, 68% Caucasian, 66% genotype [GT] 1a, 21% METAVIR F3-F4, 49% treatment-experienced) were treated with LDV/SOF. The mean duration from LT to treatment initiation was 4.8 years. The overall sustained virological response rate 12 weeks after completion of therapy (SVR12) was 96%. Patients treated with 8 or 12 weeks of LDV/SOF without RBV experienced an SVR12 rate of 100% and 96%, respectively. Calcineurin inhibitors were used in 89% of patients, and 32% of patients underwent adjustment in immunosuppression during treatment. One episode of mild rejection, responsive to an increase in immunosuppression dosage, was observed. There was no graft loss attributed to HCV treatment. Four deaths occurred unrelated to HCV treatment, and no significant serious adverse events were documented. In conclusion, SOF and LDV with or without RBV for 8, 12, or 24 weeks in post-LT patients was effective and safe with a high SVR12 rate across a spectrum of GTs and stages of fibrosis. Liver Transplantation 22 1536-1543 2016 AASLD.",
"affiliations": "Medstar Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC. ryan.m.kwok.mil@mail.mil.;Oregon Health and Science University, Portland, OR.;Division of Liver Diseases and Recanati-Miller Transplant Institute, Mount Sinai Medical Center, New York, NY.;Center for Liver Diseases, Department of Medicine, The University of Chicago Medical Center, Chicago, IL.;Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.;University of Minnesota Medical School, Minneapolis, MN.;Medstar Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC.;Medstar Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC.;Medstar Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC.;Medstar Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC.;Oregon Health and Science University, Portland, OR.;Division of Liver Diseases and Recanati-Miller Transplant Institute, Mount Sinai Medical Center, New York, NY.;Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.;University of Minnesota Medical School, Minneapolis, MN.;Division of Liver Diseases and Recanati-Miller Transplant Institute, Mount Sinai Medical Center, New York, NY.;Medstar Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC.",
"authors": "Kwok|Ryan M|RM|;Ahn|Joseph|J|;Schiano|Thomas D|TD|;Te|Helen S|HS|;Potosky|Darryn R|DR|;Tierney|Amber|A|;Satoskar|Rohit|R|;Robertazzi|Suzanne|S|;Rodigas|Colleen|C|;Lee Sang|Michelle|M|;Wiegel|Joshua|J|;Patel|Neal|N|;Gripshover|Janet|J|;Hassan|Mohamed A|MA|;Branch|Andrea|A|;Smith|Coleman I|CI|",
"chemical_list": "D000998:Antiviral Agents; D001562:Benzimidazoles; D065095:Calcineurin Inhibitors; D004338:Drug Combinations; D005449:Fluorenes; C000595958:ledipasvir, sofosbuvir drug combination; D012254:Ribavirin; D014542:Uridine Monophosphate; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.1002/lt.24614",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-6465",
"issue": "22(11)",
"journal": "Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society",
"keywords": null,
"medline_ta": "Liver Transpl",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D001562:Benzimidazoles; D065095:Calcineurin Inhibitors; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D005449:Fluorenes; D006084:Graft Rejection; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007165:Immunosuppression Therapy; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D064792:Pragmatic Clinical Trials as Topic; D012008:Recurrence; D012189:Retrospective Studies; D012254:Ribavirin; D000069474:Sofosbuvir; D014542:Uridine Monophosphate",
"nlm_unique_id": "100909185",
"other_id": null,
"pages": "1536-1543",
"pmc": null,
"pmid": "27543748",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Sofosbuvir plus ledispasvir for recurrent hepatitis C in liver transplant recipients.",
"title_normalized": "sofosbuvir plus ledispasvir for recurrent hepatitis c in liver transplant recipients"
} | [
{
"companynumb": "US-ZYDUS-013062",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEDIPASVIR\\SOFOSBUVIR"
},
"drugadditional": "3",
... |
{
"abstract": "Microdontia is one of the late effects of antineoplastic therapy in children. This study is based on the comparative histological examination of abnormal, peg-shaped premolars, erupted in a patient treated for neuroblastoma, and of non-affected teeth, extracted in a healthy child. Apart from the size, the teeth vary in tissue morphology. The number of dentinal tubules, dependent on the number of odontoblasts, is smaller in the microdontal sample when observation in the same-sized field of view is conducted. Moreover, the youngest, more than 100-micrometer-thick layer of the microdontal dentin seems to be the secondary dentin, with crispy-shaped tubules and empty spaces between them. No irregular dentin is deposited in the samples of physiologically developed teeth. The structure of cementum is different as well. Unlike regularly shaped premolars, in which typical 2-layer tissue is seen, in sections of microdontal teeth, only acellular tissue with cementoblasts overlying its surface is present. Thorough analysis of drug administration effects, which are visible in microscopic sections, and of time of anticancer treatment could provide insight into the developmental mechanisms of tooth germ formation.",
"affiliations": "Department of Pediatric Dentistry, Medical University of Silesia, Katowice, Poland.;Department of Patomorphology and Molecular Diagnostics, Medical University of Silesia, Katowice, Poland.;Department of Pediatric Dentistry, Medical University of Silesia, Katowice, Poland.",
"authors": "Jodłowska|Anna|A|;Pająk|Jacek|J|;Postek-Stefańska|Lidia|L|",
"chemical_list": "D003609:Dactinomycin; D014750:Vincristine; D003520:Cyclophosphamide",
"country": "Poland",
"delete": false,
"doi": "10.17219/dmp/95028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1644-387X",
"issue": "55(3)",
"journal": "Dental and medical problems",
"keywords": "chemotherapy; histopathology; neuroblastoma; tooth abnormalities",
"medline_ta": "Dent Med Probl",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D003520:Cyclophosphamide; D003609:Dactinomycin; D003804:Dentin; D006801:Humans; D008297:Male; D009447:Neuroblastoma; D011862:Radiography, Panoramic; D014071:Tooth Abnormalities; D014750:Vincristine",
"nlm_unique_id": "101205669",
"other_id": null,
"pages": "343-349",
"pmc": null,
"pmid": "30328313",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Microdontia after chemotherapy in a patient treated for neuroblastoma: Histopathological findings.",
"title_normalized": "microdontia after chemotherapy in a patient treated for neuroblastoma histopathological findings"
} | [
{
"companynumb": "PL-Recordati Rare Diseases Inc.-PL-R13005-19-00121",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DACTINOMYCIN"
},
"dr... |
{
"abstract": "A 37-year-old woman with a history of inflammatory bowel disease on mercaptopurine presented with a week of recurrent fever, headache, myalgias and mildly elevated serum transaminases and leucopenia. Her workup revealed primary cytomegalovirus (CMV) infection with atypical lymphocytosis, elevated viral load, positive IgM and negative IgG. Two weeks after her initial presentation, she developed odynophagia and diarrhoea prompting endoscopic evaluation with biopsies, which demonstrated CMV disease of the gastrointestinal tract. Her fever and systemic symptoms improved rapidly with initiation of intravenous ganciclovir. She was transitioned to and maintained on oral valganciclovir until two and half months after discharge when her symptoms and lab abnormalities had fully subsided.",
"affiliations": "Internal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA emeyerowitz@mgh.harvard.edu.;Anatomic Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.",
"authors": "Gong|Jingyi|J|;Meyerowitz|Eric Allan|EA|;Isidro|Raymond A|RA|;Kaye|Kenneth M|KM|",
"chemical_list": "D000998:Antiviral Agents; D015774:Ganciclovir",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-230056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(9)",
"journal": "BMJ case reports",
"keywords": "infection (gastroenterology); infections; infectious diseases; inflammatory bowel disease; pathology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D003586:Cytomegalovirus Infections; D005260:Female; D005334:Fever; D015774:Ganciclovir; D005767:Gastrointestinal Diseases; D006261:Headache; D006801:Humans; D015212:Inflammatory Bowel Diseases; D063806:Myalgia; D009894:Opportunistic Infections; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31570344",
"pubdate": "2019-09-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20890068;26893500;23347210;25684400;29255765;17029132;26811669;23326158;16954807;15496396;9335340;29507025;30876964;22723754;30050572;10530492;24763133;27682069;24613021;8994755;19571016;27472242;30031174;21788989",
"title": "Primary cytomegalovirus infection with invasive disease in a patient with inflammatory bowel disease.",
"title_normalized": "primary cytomegalovirus infection with invasive disease in a patient with inflammatory bowel disease"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0116059",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MERCAPTOPURINE"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nBone marrow failure in dyskeratosis congenita (DKC) is progressive, and allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment. However, outcomes after HCT are suboptimal because of mucosal, vascular, pulmonary, and hepatic fragility, which can be exacerbated by chemotherapy conditioning and graft-versus-host disease (GVHD). These toxicities can be mitigated by reducing the intensity of the conditioning regimen.\n\n\nMETHODS\nWe performed a retrospective analysis on pediatric patients with DKC who underwent HCT at our institution between 2008 and 2019.\n\n\nRESULTS\nWe identified nine patients (median age, 5.7 years) who underwent HCT with a fludarabine-based reduced-intensity conditioning (RIC) regimen. GVHD prophylaxis consisted of tacrolimus plus mycophenolate mofetil (MMF) (n = 8), tacrolimus/pentostatin (n = 1), or cyclosporine/MMF (n = 1). The median time to neutrophil engraftment was 19 days (range, 13-26 days), and the median time to platelet engraftment was 18 days (range, 17-43 days). Lung function, as measured by spirometry in six patients, remained stable during post-HCT observation. Six patients (67%) remain alive, with a median follow-up of 73.5 months.\n\n\nCONCLUSIONS\nBecause of toxicity after myeloablative conditioning, RIC is becoming standard for HCT in DKC. These results suggest that RIC regimen is feasible and safe for patients with DKC and does not accelerate pulmonary damage in the short-to-medium term after HCT.",
"affiliations": "Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.",
"authors": "Bhoopalan|Senthil Velan|SV|https://orcid.org/0000-0002-1402-6549;Wlodarski|Marcin|M|;Reiss|Ulrike|U|;Triplett|Brandon|B|https://orcid.org/0000-0001-8220-9980;Sharma|Akshay|A|https://orcid.org/0000-0003-3281-2081",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.29177",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "68(10)",
"journal": "Pediatric blood & cancer",
"keywords": "HCT; bone marrow transplantation; dyskeratosis congenita; hematopoietic stem cell transplantation; pulmonary function; reduced-intensity conditioning",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": null,
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e29177",
"pmc": null,
"pmid": "34086408",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Reduced-intensity conditioning-based hematopoietic cell transplantation for dyskeratosis congenita: Single-center experience and literature review.",
"title_normalized": "reduced intensity conditioning based hematopoietic cell transplantation for dyskeratosis congenita single center experience and literature review"
} | [
{
"companynumb": "US-ROCHE-2981667",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "4",
... |
{
"abstract": "Eculizumab has been shown to be efficacious in acetylcholine receptor antibody-positive (AChR+ ) Myasthenia Gravis Foundation of America (MGFA) class II, III, and IV generalized myasthenia gravis (gMG) patients. However, it has not been studied in MGFA class V gMG patients.\n\n\n\nWe report three AChR+ , refractory, MGFA class V gMG patients treated with eculizumab. MGFA class, MG-Composite (MGC) score and MG Activities of Daily Living (MG-ADL) score were assessed before and after eculizumab.\n\n\n\nTwo of three gMG patients, refractory to intravenous immunoglobulin, plasmapheresis, prednisone, and (in one case) rituximab, showed a robust response to eculizumab with marked improvement in MGFA, MG-ADL, and MGC measures. The third patient showed a partial response to eculizumab but remained on noninvasive ventilation and gastrostomy intubation. Patients 1 and 2 achieved minimal manifestation status at week 4 and week 6, respectively, and showed continued improvement on MG-ADL and MGC scores through weeks 55 and 43, respectively, with eculizumab. The third patient showed a partial response at week 10, followed by a slight decline in his MG-ADL score, but noted a slow but an incomplete improvement afterward on MG-ADL and MGC scores, possibly due to delayed eculizumab infusion.\n\n\n\nEculizumab may play a role in the treatment of patients with MGFA class V, refractory gMG. Larger studies are required to provide further evidence.",
"affiliations": "Department of Neurology, Yale University, New Haven, Connecticut, USA.;Department of Neurology, Banner University Medical Centre, Phoenix, AZ, Phoenix, Arizona, USA.;Department of Neurology, Barrow Neurological Institute. Phoenix. AZ, Phoenix, Arizona, USA.;Department of Neurology, Phoenix Children Hospital, Phoenix, Arizona, USA.;Department of Neurology, Banner University Medical Centre, Phoenix, AZ, Phoenix, Arizona, USA.;Department of Neurology, Barrow Neurological Institute. Phoenix. AZ, Phoenix, Arizona, USA.",
"authors": "Usman|Uzma|U|;Chrisman|Christina|C|;Houston|Drew|D|;Haws|Clara Chow|CC|;Wang|Alan|A|;Muley|Suraj|S|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D051056:Complement Inactivating Agents; D000069283:Rituximab; C481642:eculizumab",
"country": "United States",
"delete": false,
"doi": "10.1002/mus.27326",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-639X",
"issue": "64(2)",
"journal": "Muscle & nerve",
"keywords": "\nMGC, MGFA; eculizumab; myasthenia gravis; ventilator-dependent",
"medline_ta": "Muscle Nerve",
"mesh_terms": "D000203:Activities of Daily Living; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D051056:Complement Inactivating Agents; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis; D000069283:Rituximab; D012122:Ventilators, Mechanical",
"nlm_unique_id": "7803146",
"other_id": null,
"pages": "212-215",
"pmc": null,
"pmid": "34008175",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The use of eculizumab in ventilator-dependent myasthenia gravis patients.",
"title_normalized": "the use of eculizumab in ventilator dependent myasthenia gravis patients"
} | [
{
"companynumb": "US-GYP-000338",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "IMMUNE GLOBULIN NOS"
},
"drugadditional": null,
... |
{
"abstract": "Immune-checkpoint inhibitors (ICI) are monoclonal antibodies which target molecules to enhance antitumor response. Several adverse events have been described and the major ICI-related endocrinopathies are thyroid dysfunction and hypophysitis. Its occurrence has been associated with improved outcomes, but it is still to be proven. We performed a retrospective study of patients treated with ICI between 2014 and 2019 at an oncologic center to characterize thyroid function test abnormalities (TFTA) and to evaluate clinical outcomes. We excluded patients without regular monitoring of thyroid function, with previous thyroid or pituitary disease, previous head/neck radiotherapy and who performed only one ICI cycle. We included 161 of 205 patients treated with pembrolizumab, nivolumab or ipilimumab for several neoplasms, with a median duration of 18.9 weeks (9.1-42.6) of ICI treatment and 49.4 weeks (26.5-75.8) of follow-up. New-onset TFTA was diagnosed in 18% of patients (n = 29), in median at 10.6 weeks (6.1-31.1) of ICI therapy. On the whole, 8.7% had primary hypothyroidism, 4.3% central hypothyroidism, 2.5% biphasic thyroiditis and 2.5% thyrotoxicosis. Patients who experienced primary or central thyroid dysfunction had a significantly improved overall response rate (58.6% vs 34.2%, p = 0.015) and overall survival (3.27 vs 1.76 years, p = 0.030), compared to the control group. The risk of mortality was two times higher for control group (adjusted HR = 2.43, 95% CI 1.13-5.23, p = 0.023). This study recognizes that primary and central thyroid dysfunction can be a predictive clinical biomarker of a better response to ICI across several neoplasms.",
"affiliations": "Department of Endocrinology, Hospital Pedro Hispano, Matosinhos Local Health Unit, Matosinhos, Portugal. joanalferreira@gmail.com.;Department of Endocrinology, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal.;Department of Endocrinology, Instituto Português de Oncologia de Coimbra Francisco Gentil, Coimbra, Portugal.;Department of Nuclear Medicine, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal.;Department of Nuclear Medicine, Hospital Garcia de Orta, Almada, Portugal.;Department of Endocrinology, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal.;Department of Endocrinology, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal.;Department of Nuclear Medicine, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal.;Department of Nuclear Medicine, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal.;Department of Endocrinology, Hospital Pedro Hispano, Matosinhos Local Health Unit, Matosinhos, Portugal.;Department of Endocrinology, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal.",
"authors": "Lima Ferreira|Joana|J|http://orcid.org/0000-0002-8405-7682;Costa|Cláudia|C|;Marques|Bernardo|B|;Castro|Sofia|S|;Victor|Margarida|M|;Oliveira|Joana|J|;Santos|Ana Paula|AP|;Sampaio|Inês Lucena|IL|;Duarte|Hugo|H|;Marques|Ana Paula|AP|;Torres|Isabel|I|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00262-020-02664-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-7004",
"issue": "70(2)",
"journal": "Cancer immunology, immunotherapy : CII",
"keywords": "Anti-CTLA-4; Anti-PD-1; Hypophysitis; Immunotherapy; Survival; Thyroid",
"medline_ta": "Cancer Immunol Immunother",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008297:Male; D016019:Survival Analysis; D013959:Thyroid Diseases; D013960:Thyroid Function Tests",
"nlm_unique_id": "8605732",
"other_id": null,
"pages": "299-309",
"pmc": null,
"pmid": "32712715",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": "29238906;22437870;24188664;29990692;30242549;27998967;31542865;27136138;27472273;24767731;27269740;30937112;31518074;29187509;30805887;31005502;29769383;31461358;29043574;25078147;25416723;28891423;28826822;30120013;31730012;31130304;30693099;30184160;29313945;30057972;29296533;19078956;33108969;17982122;22109345;21106722;19671877;5791828",
"title": "Improved survival in patients with thyroid function test abnormalities secondary to immune-checkpoint inhibitors.",
"title_normalized": "improved survival in patients with thyroid function test abnormalities secondary to immune checkpoint inhibitors"
} | [
{
"companynumb": "PT-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-049416",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "OBJECTIVE\nTo compare overall survival and toxicities after yttrium-90 (90Y) radioembolization and chemoembolization with drug-eluting embolics (DEE) in patients with infiltrative hepatocellular carcinoma (HCC).\n\n\nMETHODS\nRetrospective review of 50 patients with infiltrative HCC without main portal vein invasion who were treated with 90Y radioembolization (n = 26) or DEE chemoembolization (n = 24) between March 2007 and August 2012 was completed. Infiltrative tumors were defined by cross-sectional imaging as masses that lacked well-demarcated boundaries, and treatment allocations were made by a multidisciplinary tumor board. Median age was 63 years; median tumor diameter was 9.0 cm; and there were no significant differences between groups in performance status, severity of liver disease, or HCC stage. Toxicities were graded by Common Terminology Criteria for Adverse Events v4.03. Overall survival from treatment was assessed by Kaplan-Meier analysis, with analysis of potential predictors of survival with log-rank test.\n\n\nRESULTS\nThere was no difference in the average number of procedures performed in each treatment group (DEE, 1.5 ± 1.1; 90Y, 1.6 ± 0.5; P = .97), and technical success was achieved in all cases. Abdominal pain (73% vs 33%; P = .004) and fever (38% vs 8%; P = .01) were more frequent after DEE chemoembolization. There was no significant difference in median overall survival between treatment groups after treatment (DEE, 9.9 months; 90Y, 8.1 months; P = .11).\n\n\nCONCLUSIONS\n90Y radioembolization and DEE chemoembolization provided similar overall survival in the treatment of infiltrative HCC without main portal vein invasion. Abdominal pain and fever were more frequent after DEE chemoembolization.",
"affiliations": "Department of Radiology, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, TX 75235. Electronic address: josephlmcdevitt@icloud.com.;Department of Radiology, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, TX 75235.;Vascular and Interventional Radiology, Cleveland Clinic, Cleveland, Ohio.;Vascular and Interventional Radiology, Cleveland Clinic, Cleveland, Ohio.;Vascular and Interventional Radiology, Cleveland Clinic, Cleveland, Ohio.;Vascular and Interventional Radiology, Cleveland Clinic, Cleveland, Ohio.;Vascular and Interventional Radiology, Cleveland Clinic, Cleveland, Ohio.;Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio.;Transplant Surgery, Cleveland Clinic, Cleveland, Ohio.;Solid Tumor Oncology, Cleveland Clinic, Cleveland, Ohio.;Division of Vascular and Interventional Radiology, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, TX 75235.;Division of Vascular and Interventional Radiology, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, TX 75235.;Vascular and Interventional Radiology, Cleveland Clinic, Cleveland, Ohio.",
"authors": "McDevitt|Joseph L|JL|;Alian|Ali|A|;Kapoor|Baljendra|B|;Bennett|Stacy|S|;Gill|Amanjit|A|;Levitin|Abraham|A|;Sands|Mark|M|;Narayanan Menon|K V|KV|;Aucejo|Federico N|FN|;Estfan|Bassam|B|;Pillai|Anil K|AK|;Kalva|Sanjeeva P|SP|;McLennan|Gordon|G|",
"chemical_list": "D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; C000615496:Yttrium-90",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jvir.2017.05.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1051-0443",
"issue": "28(10)",
"journal": "Journal of vascular and interventional radiology : JVIR",
"keywords": null,
"medline_ta": "J Vasc Interv Radiol",
"mesh_terms": "D001706:Biopsy; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D019275:Radiopharmaceuticals; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D015021:Yttrium Radioisotopes",
"nlm_unique_id": "9203369",
"other_id": null,
"pages": "1371-1377",
"pmc": null,
"pmid": "28689934",
"pubdate": "2017-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Single-Center Comparison of Overall Survival and Toxicities in Patients with Infiltrative Hepatocellular Carcinoma Treated with Yttrium-90 Radioembolization or Drug-Eluting Embolic Transarterial Chemoembolization.",
"title_normalized": "single center comparison of overall survival and toxicities in patients with infiltrative hepatocellular carcinoma treated with yttrium 90 radioembolization or drug eluting embolic transarterial chemoembolization"
} | [
{
"companynumb": "US-JNJFOC-20171104811",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "Concurrent anthracycline and taxane is an effective and efficient way to deliver neoadjuvant chemotherapy for HER2-negative breast cancers. Data on efficacy and tolerance to 6 cycles of concurrent docetaxel, epirubicin, and cyclophosphamide (TEC) is limited.\n\n\n\nAll patients with HER2-negative breast cancers who received neoadjuvant TEC from January 2013 to December 2019 were reviewed.\n\n\n\nA total of 71 patients [57 luminal B disease; 14 triple negative breast cancer (TNBC)] received neoadjuvant TEC with prophylactic granulocyte colony-stimulating factor (G-CSF). The pathological complete response (pCR) rate was 26.3% and 28.6% for luminal B and TNBC, respectively. With median follow-up of 48.9 months, 3 years disease-free survival was 85.9%, and 3 years overall survival was 89.6%. Non-hematological toxicities were common but the majority was grade 1 or 2. The most common grade 3 or 4 toxicity were hematological, including neutropenia (26.8%) and anemia (15.5%). There was no cardiotoxicity observed. Half of the patients had at least one dose reduction but all patients completed the planned 6 cycles and had breast surgery done.\n\n\n\nSix cycles of TEC with prophylactic G-CSF is an effective and tolerable neoadjuvant regime for HER2-negative breast cancers. Hematological toxicities were the most common toxicities. Although many patients required dose reduction, all patients completed treatment and there was no observed cardiotoxicity.",
"affiliations": "Division of Hematology and Medical Oncology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong.;Division of Hematology and Medical Oncology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong.;Division of Hematology and Medical Oncology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong.;Division of Hematology and Medical Oncology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong.;Division of Hematology and Medical Oncology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong.;Department of Surgery, Hong Kong Sanatorium Hospital, Happy Valley, Hong Kong.;Department of Surgery, Hong Kong Sanatorium Hospital, Happy Valley, Hong Kong.;Department of Surgery, Queen Mary Hospital, Pok Fu Lam, Hong Kong.;Department of Surgery, Queen Mary Hospital, Pok Fu Lam, Hong Kong.;Division of Hematology and Medical Oncology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong. jwychiu@hku.hk.",
"authors": "Li|Bryan|B|;Yau|Thomas|T|;Leung|Roland|R|;Kwok|Gerry|G|;Tsang|Josephine|J|;Cheung|Polly|P|;Wong|T T|TT|;Suen|Dacita|D|;Kwong|Ava|A|;Chiu|Joanne W|JW|0000-0002-8320-3166",
"chemical_list": "D000077143:Docetaxel; D015251:Epirubicin; D003520:Cyclophosphamide; D018719:Receptor, ErbB-2",
"country": "United States",
"delete": false,
"doi": "10.1007/s12325-021-01933-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0741-238X",
"issue": "38(12)",
"journal": "Advances in therapy",
"keywords": "Anthracycline; Breast cancer; Neoadjuvant therapy; Pathologic complete response; TEC; Taxane",
"medline_ta": "Adv Ther",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D003520:Cyclophosphamide; D000077143:Docetaxel; D015251:Epirubicin; D005260:Female; D006801:Humans; D020360:Neoadjuvant Therapy; D018719:Receptor, ErbB-2; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms",
"nlm_unique_id": "8611864",
"other_id": null,
"pages": "5752-5762",
"pmc": null,
"pmid": "34699004",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": "28484080;30655846",
"title": "Neoadjuvant Therapy with Concurrent Docetaxel, Epirubicin, and Cyclophosphamide (TEC) in High-Risk HER2-Negative Breast Cancers.",
"title_normalized": "neoadjuvant therapy with concurrent docetaxel epirubicin and cyclophosphamide tec in high risk her2 negative breast cancers"
} | [
{
"companynumb": "HK-AMGEN-HKGSP2022042117",
"fulfillexpeditecriteria": "2",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "4",
... |
{
"abstract": "Although the combination of fludarabine and high-dose melphalan (FLU/MEL) has been widely used in allogeneic stem cell transplantation, high-dose MEL causes life-threatening adverse events, especially in elderly patients. To reduce the toxicity of MEL without losing its antileukemic effect, we formulated a regimen comprising FLU (125 mg/m2), MEL (100 mg/m2), and a non-myeloablative busulfan dosage [4 mg/kg orally (oral) or 3.2 mg/kg intravenously (iv); FLU/MEL/BU]. We retrospectively analyzed 32 patients with myeloid malignancies who received FLU/MEL/BU at our institute. Median age was 59 years and the median observation period after allo-SCT was 8.2 years. The disease status of most of the patients (97%) at transplantation was controlled. The rate of neutrophil engraftment was 93.3%. The 5-year overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), and relapse rate (RR) were 68.5%, 62.1%, 22.0%, and 15.9%, respectively, in all patients. Notably, the outcome of FLU/MEL/iv BU was excellent, with the 5-year OS and DFS being 75.6% and 70.8%, respectively, accompanied by a reduced 5-year NRM and RR of 19.3% and 9.8%, respectively. In conclusion, FLU/MEL/BU, particularly FLU/MEL/iv BU, has curative potential for controlled myeloid malignancies.",
"affiliations": "Department of Hematology/Oncology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, 710-8602, Japan. uedat@bldon.med.osaka-u.ac.jp.;Department of Hematology/Oncology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, 710-8602, Japan.;Department of Hematology/Oncology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, 710-8602, Japan.;Department of Hematology/Oncology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, 710-8602, Japan.;Department of Hematology/Oncology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, 710-8602, Japan.;Department of Hematology/Oncology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, 710-8602, Japan.;Department of Hematology/Oncology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, 710-8602, Japan.;Department of Hematology/Oncology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, 710-8602, Japan.",
"authors": "Ueda|Tomoaki|T|;Jo|Tomoyasu|T|;Okada|Kazuya|K|;Arai|Yasuyuki|Y|;Sato|Takayuki|T|;Maeda|Takeshi|T|;Onishi|Tatsuhito|T|;Ueda|Yasunori|Y|",
"chemical_list": "D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine; D008558:Melphalan",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-019-02763-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "111(2)",
"journal": "International journal of hematology",
"keywords": "Allogeneic stem cell transplantation; Busulfan; Conditioning regimen; Melphalan; Myeloid malignancy",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002066:Busulfan; D006801:Humans; D007951:Leukemia, Myeloid; D008558:Melphalan; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D014740:Vidarabine",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "247-255",
"pmc": null,
"pmid": "31701479",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
"references": "24065243;24056743;16338616;27164061;7581076;17415646;27345142;16384925;16314618;11304772;9070469;28890406;24621081;26612281;15668755;23872739;11535508;17139495;12393448;17382251;21263156;11157478;22609886;26437064;23208313;30448938;25854336;27470290;26642343;25545836;16109776;30135184;19349956;17047152;21423118;17690701;25531281;16009946;24978140",
"title": "Curative potential of fludarabine, melphalan, and non-myeloablative dosage of busulfan in elderly patients with myeloid malignancy.",
"title_normalized": "curative potential of fludarabine melphalan and non myeloablative dosage of busulfan in elderly patients with myeloid malignancy"
} | [
{
"companynumb": "NVSC2020JP062144",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN CALCIUM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe emergence of immune checkpoint inhibitors (ICIs) has brought about a paradigm shift in cancer treatment as the use of these drugs has become more frequent and for a longer duration. As a result of T-cell-mediated inflammation at the programmed cell death-1, programmed death-ligand-1, and cytotoxic T-lymphocyte antigen-4 pathways, immune-related adverse events (irAEs) occur in various organs and can cause a rare but potentially induced cardiotoxicity. Although irAEs are associated with the efficacy of ICI therapy and better prognosis, there is limited information about the correlation between irAEs and cardiotoxicity and whether the benefits of irAEs apply to patients with underlying cardiovascular disease. This study aimed to investigate the association of irAEs and treatment efficacy in patients undergoing ICI therapy with and without a cardiovascular history.\n\n\nMETHODS\nWe performed a retrospective review of the medical records of 409 consecutive patients who received ICI therapy from September 2014 to October 2019.\n\n\nRESULTS\nMedian patient age was 69 years (29.6% were female). The median follow-up period was 278 days. In total, 69 (16.9%) patients had a history of any cardiovascular disease and 14 (3.4%) patients experienced cardiovascular irAEs after ICI administration. The rate of cardiovascular irAEs was higher in patients with prior non-cardiovascular irAEs than without. The prognosis of patients with irAEs ( +) was significantly better than that of the patients without irAEs (P < 0.001); additionally, this tendency did not depend on the presence or absence of a cardiovascular history. Furthermore, the Cox proportional hazards analysis revealed that irAEs were an independent predictor of mortality.\n\n\nCONCLUSIONS\nAlthough cardiovascular irAEs may be related to prior non-cardiovascular irAEs under ICI therapy, the occurrence of irAEs had a better prognostic impact and this tendency was not affected by cardiovascular history.",
"affiliations": "Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan. ryota.m0726@med.nagoya-u.ac.jp.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.;Department of Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.;Department of Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.",
"authors": "Kazama|Shingo|S|;Morimoto|Ryota|R|http://orcid.org/0000-0003-0931-3188;Kimura|Yuki|Y|;Shibata|Naoki|N|;Ozaki|Reina|R|;Araki|Takashi|T|;Mizutani|Takashi|T|;Oishi|Hideo|H|;Arao|Yoshihito|Y|;Kuwayama|Tasuku|T|;Hiraiwa|Hiroaki|H|;Kondo|Toru|T|;Furusawa|Kenji|K|;Shimokata|Tomoya|T|;Okumura|Takahiro|T|;Bando|Yasuko K|YK|;Ando|Yuichi|Y|;Murohara|Toyoaki|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40959-021-00112-z",
"fulltext": "\n==== Front\nCardiooncology\nCardiooncology\nCardio-oncology\n2057-3804\nBioMed Central London\n\n112\n10.1186/s40959-021-00112-z\nResearch\nPrognostic impact of immune-related adverse events on patients with and without cardiovascular disease: a retrospective review\nKazama Shingo 1\nhttp://orcid.org/0000-0003-0931-3188\nMorimoto Ryota ryota.m0726@med.nagoya-u.ac.jp\n\n1\nKimura Yuki 1\nShibata Naoki 1\nOzaki Reina 1\nAraki Takashi 1\nMizutani Takashi 1\nOishi Hideo 1\nArao Yoshihito 1\nKuwayama Tasuku 1\nHiraiwa Hiroaki 1\nKondo Toru 1\nFurusawa Kenji 1\nShimokata Tomoya 2\nOkumura Takahiro 1\nBando Yasuko K. 1\nAndo Yuichi 2\nMurohara Toyoaki 1\n1 grid.27476.30 0000 0001 0943 978X Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550 Japan\n2 grid.437848.4 0000 0004 0569 8970 Department of Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan\n6 7 2021\n6 7 2021\n2021\n7 2626 2 2021\n25 6 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nThe emergence of immune checkpoint inhibitors (ICIs) has brought about a paradigm shift in cancer treatment as the use of these drugs has become more frequent and for a longer duration. As a result of T-cell-mediated inflammation at the programmed cell death-1, programmed death-ligand-1, and cytotoxic T-lymphocyte antigen-4 pathways, immune-related adverse events (irAEs) occur in various organs and can cause a rare but potentially induced cardiotoxicity. Although irAEs are associated with the efficacy of ICI therapy and better prognosis, there is limited information about the correlation between irAEs and cardiotoxicity and whether the benefits of irAEs apply to patients with underlying cardiovascular disease. This study aimed to investigate the association of irAEs and treatment efficacy in patients undergoing ICI therapy with and without a cardiovascular history.\n\nMethods\n\nWe performed a retrospective review of the medical records of 409 consecutive patients who received ICI therapy from September 2014 to October 2019.\n\nResults\n\nMedian patient age was 69 years (29.6% were female). The median follow-up period was 278 days. In total, 69 (16.9%) patients had a history of any cardiovascular disease and 14 (3.4%) patients experienced cardiovascular irAEs after ICI administration. The rate of cardiovascular irAEs was higher in patients with prior non-cardiovascular irAEs than without. The prognosis of patients with irAEs ( +) was significantly better than that of the patients without irAEs (P < 0.001); additionally, this tendency did not depend on the presence or absence of a cardiovascular history. Furthermore, the Cox proportional hazards analysis revealed that irAEs were an independent predictor of mortality.\n\nConclusions\n\nAlthough cardiovascular irAEs may be related to prior non-cardiovascular irAEs under ICI therapy, the occurrence of irAEs had a better prognostic impact and this tendency was not affected by cardiovascular history.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s40959-021-00112-z.\n\nKeywords\n\nImmune checkpoint inhibitors\nImmune-related adverse events\nCardiotoxicity\nPrognosis\nCardiovascular history\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nEmergence of immune checkpoint inhibitors (ICIs) has led to a paradigm shift in cancer treatment as their use continues to expand [1, 2]. ICI administration has substantially improved clinical outcomes across a range of cancer types, particularly in malignant melanoma, non-small cell lung cancer, and renal cancer. ICIs suppress immune reactions, but their suppressive mechanism can be decreased by administering inhibitory antibodies against these molecules [1]. This enhances the body’s natural immune response to cancer, allowing it to kill cancer cells. Conversely, activated T-cell responses may not be specific to cancer cells and might target normal tissue, leading to immune-related adverse events (irAEs) [3]. IrAEs have reportedly occurred in nearly all organs and are particularly common in non-cardiovascular organs such as the colon, lungs, endocrine glands, skin, and liver. Recently, several studies have reported that the development of irAEs was associated with clinical benefits for patients receiving ICI therapy [4–6]. Meanwhile, cancer and cardiovascular diseases often coexist because of shared risk factors such as hypertension, obesity, smoking, and diabetes [7], and multiple types of anti-cancer drugs and therapies can cause cardiovascular disorders. When accelerated T-cell-mediated inflammation in the cardiovascular system occurs during ICI therapy, cardiotoxicity associated with ICI treatment such as myocarditis, vasculitis, pericardial diseases, left ventricular systolic dysfunction, rhythm disorders, and acute coronary syndrome occurred infrequently [8–15]; moreover, myocarditis in particular can lead to fatal consequences [16]. Although the dense myocardial capillary network that interacts with immune cells and the myocardium is susceptible to immune reactions with the onset of non-cardiovascular irAEs [17], little is known about the relationship between non-cardiovascular irAEs and cardiotoxicity. Furthermore, it is unclear whether the occurrence of irAEs is a good prognostic factor even in the presence of cardiovascular disease in patients receiving ICI therapy. Therefore, we performed a detailed investigation of irAEs including the presence of cardiotoxicity under ICI therapy and the correlation between irAEs and prognosis with and without a history of cardiovascular disease.\n\nMethods\n\nStudy design and population\n\nWe retrospectively reviewed the medical records of consecutive patients who received their first ICI administration from September 2014 to October 2019. All patients who received ICIs were enrolled. In principle, ICIs were used for cancers in which the primary lesion was unresectable and for recurrent or irreversible cancers. Patient characteristics before ICI administration and the subsequent prognosis or occurrence of adverse events were evaluated. We obtained prior approval that the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki from the Ethics Committee of Nagoya University Hospital (approval number 2019–0176).\n\nType of ICI\n\nThe ICIs were chosen from the following types: programmed cell death-1 (PD-1) inhibitors (nivolumab or pembrolizumab), programmed death-ligand-1 (PD-L1) inhibitors (atezolizumab or durvalumab), and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors (ipilimumab). The type and dose of ICI had been determined by the attending physician of each department, with some administered as part of a combination therapy.\n\nDefinition of non-cardiovascular and cardiovascular irAEs\n\nThe irAEs were diagnosed according to the American Society of Clinical Oncology (ASCO) guidelines [18]. According to medical records, patients who had clearly been described as experiencing an irAE of grades 2–4, as defined in the ASCO guidelines, were considered to have developed irAEs. Cardiovascular irAEs included myocarditis, pericarditis, acute coronary syndrome, arrhythmia, heart failure, vasculitis, and venous thromboembolism with over mild-to-moderate symptoms post ICI therapy.\n\nDefinition of cardiovascular history\n\nCardiovascular history was defined as the presence of a prior diagnosis of a cardiovascular disease before ICI administration, such as with coronary artery disease, heart failure, arrhythmia, venous thromboembolism, and pericardial disease.\n\nOutcome\n\nThe primary outcome was the occurrence of all-cause mortality within the follow-up period.\n\nStatistical analysis\n\nContinuous data were presented as medians with interquartile ranges (IQRs) and were compared with the Mann–Whitney U test. Categorical variables were expressed as counts (percentages) and were compared with the Chi-square test or Fisher’s exact test. Kaplan–Meier curves and the log-rank test were used to quantify the relationship between the occurrence of irAEs and the survival rate. The Cox proportional hazards regression analysis was performed to identify the predictors of all-cause mortality. Additionally, a landmark analysis at 3 months after initiating ICI treatment was performed to adjust for the effects of early progression or death, in which patients who experienced events in the first 3 months were excluded. All statistical analyses were performed using R version 3.5.2 (R Foundation for Statistical Computing, Vienna, Austria), and statistical significance was accepted for P-values < 0.05.\n\nResults\n\nPatient characteristics at baseline\n\nDuring the study period, 412 patients with cancer received their first ICI administration. Of these patients, three who lacked adequate data were excluded. Thus, 409 patients were investigated in this study. Figure 1 shows the type of ICI administered. Nivolumab was the most commonly used ICI, followed by pembrolizumab and atezolizumab, and three patients received a dual therapy. The patient characteristics are presented in Table 1. The median age was 69 years, and 121 (29.6%) patients were female. In total, 162 (39.6%), 74 (18.1%), and 72 (17.6%) patients had a medical history of hypertension, diabetes mellitus, and dyslipidemia, respectively, and 69 (16.9%) patients had a history of any cardiovascular disease. Furthermore, 34 (8.3%), 24 (5.9%), 5 (1.2%), 8 (2.0%), and 3 (0.7%) patients had a history of coronary artery disease, arrhythmia, heart failure, venous thromboembolism, and pericardial disease, respectively. Of the 69 patients, 57 (82.6%) patients were followed up by cardiologists or their family physicians, and 48 (69.6%) patients continued to receive medication for cardiovascular comorbidities during ICI therapy. The median time from the onset of cardiovascular disease to the start of ICI therapy was 656 (314–1366) days.Fig. 1 All types and the number of immune checkpoint inhibitors (ICIs). Nivolumab was the most commonly used ICI, followed by pembrolizumab and atezolizumab. Forty-three patients experienced a change in the type of ICI they were administered, and three patients received dual ICI therapy\n\nTable 1 Patient characteristics at baseline\n\n\tAll\n(n = 409)\tirAEs ( +)\n(n = 138)\tirAEs (-)\n(n = 271)\tP value\t\nAge, years\t69 (60–74)\t70 (60–74)\t69 (60–74)\t0.32\t\nGender (male)\t288 (70.4)\t94 (68.7)\t194 (71.6)\t0.49\t\nBMI, kg/m2\t20.9 (18.1–23.4)\t21.7 (18.5–24.0)\t20.5 (17.9–23.2)\t0.04\t\nPulse rate, bpm\t82 (73–93)\t81 (71–91)\t84 (74–94)\t0.12\t\nSystolic blood pressure, mmHg\t120 (107–134)\t123 (111–134)\t118 (106–133)\t0.14\t\nDiastolic blood pressure, mmHg\t72 (64–81)\t72 (64–81)\t72 (64–82)\t0.70\t\nCancer type\t\n Non-small cell lung cancer\t170 (41.6)\t59 (42.8)\t111 (41.0)\t0.75\t\n Malignant melanoma\t82 (20.0)\t42 (30.4)\t40 (14.8)\t < 0.01\t\n Renal cancer\t43 (10.5)\t20 (14.5)\t23 (8.5)\t0.09\t\n Stomach cancer\t35 (8.6)\t4 (2.9)\t31 (11.4)\t0.003\t\n Pharyngeal cancer\t21 (5.1)\t3 (2.2)\t18 (6.6)\t0.059\t\n Paranasal cancer\t7 (1.7)\t2 (1.4)\t5 (1.8)\t1\t\n Tongue cancer\t7 (1.7)\t1 (0.7)\t6 (2.2)\t0.43\t\n Bladder cancer\t6 (1.5)\t1 (0.7)\t5 (1.8)\t0.67\t\n Mesothelioma\t5 (1.2)\t0 (0)\t5 (1.8)\t0.17\t\n Other cancer\t33 (8.1)\t6 (4.3)\t27 (10.0)\t0.056\t\nComorbidity\t\n Hypertension\t162 (39.6)\t60 (43.5)\t102 (37.6)\t0.29\t\n Diabetes mellitus\t74 (18.1)\t27 (19.6)\t47 (17.3)\t0.59\t\n Dyslipidemia\t72 (17.6)\t31 (22.5)\t41 (15.1)\t0.075\t\nCardiovascular history\t\n Coronary artery disease\t34 (8.3)\t15 (10.9)\t19 (7.0)\t0.19\t\n Arrythmia\t24 (5.9)\t11 (8.0)\t13 (4.8)\t0.27\t\n Heart failure\t5 (1.2)\t2 (1.4)\t3 (1.1)\t1\t\n Venous thrombosis\t8 (2.0)\t0 (0)\t8 (3.0)\t0.06\t\n Pericardial disease\t3 (0.7)\t0 (0)\t3 (1.1)\t0.55\t\nMedication\t\n ACE-I/ARB\t81 (19.8)\t35 (25.4)\t47 (17.3)\t0.067\t\n Beta-blockers\t34 (8.3)\t15 (10.9)\t19 (7.0)\t0.26\t\n Ca-channel blockers\t118 (28.9)\t43 (31.2)\t75 (27.7)\t0.49\t\n Statins\t57 (13.9)\t23 (16.7)\t34 (12.5)\t0.29\t\n Diuretics\t28 (6.8)\t6 (4.3)\t27 (10.0)\t0.21\t\nLaboratory measurements\t\n TP, mg/dL\t6.8 (6.3–7.1)\t6.8 (6.5–7.0)\t6.7 (6.3–7.2)\t0.37\t\n Alb, mg/dL\t3.7 (3.3–4.0)\t3.8 (3.4–4.1)\t3.7 (3.2–4.0)\t0.01\t\n Cre, mg/dL\t0.79 (0.65–1.00)\t0.78 (0.64–1.00)\t0.79 (0.65–1.00)\t0.91\t\n CRP, md/dL\t0.42 (0.10—1.80)\t0.23 (0.07—1.12)\t0.56 (0.13 – 2.28)\t0.004\t\n WBC, /103\t6.0 (4.9—7.7)\t5.9 (4.9 – 7.3)\t6.0 (4.9—7.8)\t0.44\t\n Hb, mg/dL\t11.8 (10.4–13.0)\t12.0 (10.9–13.2)\t11.7 (10.3–12.9)\t0.033\t\nChest radiography\t\n CTR, %\t46.5 (42.6–50.1)\t46.8 (42.8–50.2)\t46.3 (42.5–50.1)\t0.56\t\nirAEs immune-Related Adverse Events, BMI body mass index, ACE-I angiotensin-converting-enzyme inhibitor, ARB Angiotensin II Receptor Blocker, TP total protein, Alb albumin, Cre creatinine, CRP C-reactive protein, WBC white blood cell, Hb hemoglobin, CTR cardiothoracic ratio\n\nWhen divided into two groups according to the presence or absence of irAEs, no significant intergroup differences were found in terms of age, sex, or comorbidity. The irAE ( +) group had a significantly higher proportion of patients with melanoma and a lower proportion of patients with stomach cancer than the irAE ( −) group. Moreover, body mass index and albumin and hemoglobin levels were significantly higher and c-reactive protein levels were lower in the irAE ( +) group than in the irAE ( −) group.\n\nSummary of non-cardiovascular and cardiovascular irAEs\n\nA total of 159 irAEs (grades 2–4) occurred in 138 (33.7%) patients, of whom 20 had multiple irAEs. The details of the irAEs classified according to ASCO guidelines are shown in Table 2. Endocrine toxicities, including destructive thyroiditis and hypophysitis, were the most common irAEs, followed by gastrointestinal toxicities such as colitis and liver dysfunction. Figure 2 shows the time to irAE onset after the initial administration of ICIs. The median length of time from the first ICI administration to the onset of the irAE was 71 (28–161) days. Myocardial vasculitis developed 263 days after the first ICI administration, and fulminant myocarditis developed 495 days after the first ICI administration. Furthermore, 14 (3.4%) patients experienced some cardiovascular irAEs after ICI administration and required consultation with a cardiologist (Table 3). Arrhythmias were the most common of these irAEs, and cardiologist intervention was required by 3 patients with angina pectoris, 2 with pericardial effusion, 1 with pulmonary embolism, and 1 with heart failure. Fulminant myocarditis developed in one patient with malignant melanoma, and myocardial vasculitis developed in one patient with melanoma. Among the 14 patients, 9 (64.3%) with cardiovascular irAEs presented with prior grade 2–4 irAEs at other organs, and the median length of time from non-cardiovascular irAEs to the onset of cardiovascular irAEs was 74 (58–246) days. We compared cardiovascular irAEs in patients with and without prior non-cardiovascular irAE, the incidence rate of cardiovascular irAEs was significantly higher in patients with prior non-cardiovascular irAEs (P = 0.017) (Table 4).Table 2 Immune-related adverse events (Grade 2–4)\n\n\tAll\tG2\tG3\tG4\t\n1.0 Skin toxicities\t\n Rash/Dermatitis\t18 (13.0)\t17 (12.3)\t1 (0.7)\t0 (0)\t\n2.0 Gastrointestinal toxicities\t\n Colitis\t17 (12.3)\t11 (8.0)\t6 (4.3)\t0 (0)\t\n Hepatitis\t17 (12.3)\t8 (5.8)\t7 (5.1)\t2 (1.4)\t\n3.0 Lung toxicities\t\n Pneumonitis\t29 (21.0)\t21 (15.2)\t8 (5.8)\t0 (0)\t\n4.0 Endocrine toxicities\t\n Hyperthyroidism\t35 (25.4)\t33 (23.9)\t2 (1.4)\t0 (0)\t\n Adrenal insufficiency\t3 (2.2)\t3 (2.2)\t0 (0)\t0 (0)\t\n Pituitary hypophystis\t16 (11.6)\t12 (8.7)\t4 (2.9)\t0 (0)\t\n Diabetes\t2 (1.4)\t0 (0)\t1 (0.7)\t1 (0.7)\t\n5.0 Musculoskeletal toxicities\t\n Arthritis\t1 (0.7)\t1 (0.7)\t0 (0)\t0 (0)\t\n Myositis\t1 (0.7)\t1 (0.7)\t0 (0)\t0 (0)\t\n6.0 Renal toxicities\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t\n7.0 Nervous system toxities\t\n Optic neuritis\t2 (1.4)\t2 (1.4)\t0 (0)\t0 (0)\t\n8.0 Hematologic toxicities\t\n Autoimmune hemolytic anemia\t3 (2.2)\t0 (0)\t3 (2.2)\t0 (0)\t\n Lymphopenia\t1 (0.7)\t0 (0)\t1 (0.7)\t0 (0)\t\n9.0 Cardiovascular toxicities\t\n Myocarditis\t1 (0.7)\t0 (0)\t0 (0)\t1 (0.7)\t\n Vasculitis\t1 (0.7)\t0 (0)\t1 (0.7)\t0 (0)\t\n Pericardial effusion\t2 (1.4)\t0 (0)\t2 (1.4)\t0 (0)\t\n Arrhythmia\t5 (3.6)\t0 (0)\t4 (2.9)\t1 (0.7)\t\n Angina pectoris\t3 (2.2)\t0 (0)\t2 (1.4)\t1 (0.7)\t\n Heart failure\t1 (0.7)\t0 (0)\t0 (0)\t1 (0.7)\t\n Pulmonary embolism\t1 (0.7)\t0 (0)\t0 (0)\t1 (0.7)\t\n10.0 Ocular toxicities\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t\n\nFig. 2 Time to the onset of immune-related adverse events (irAEs) after the first immune checkpoint inhibitor (ICI) administration. The median time from the first ICI administration to the onset of an irAE was 77 (31–168) days\n\nTable 3 Summary of cardiovascular irAEs\n\nCase\tCardiovascular complications\tAge (years), sex\tMalignancy\tICI\tDays from first ICI administration to cardiovascular irAEs\tDays from non-cardiovascular irAEs to cardiovascular irAEs\tManagement\tOutcome\t\n1\tPaf\t66, M\tRenal cancer\tNivolumab\t64\t15\tPilsicainide\tSurvived\t\n2\tPaf\t71, M\tNSCLC\tPembrolizumab\t35\t25\tAnticoagulant therapy\tSurvived\t\n3\tAFL\t44, F\tNSCLC\tNivolumab\t4\t(-)\tBisoprolol\tCancer death\t\n4\tPSVT\t72, F\tNSCLC\tNivolumab\t89\t65\tBisoprolol\tCancer death\t\n5\tVT\t71, M\tMelanoma\tPembrolizumab\t6\t(-)\tCatheter ablation\tSurvived\t\n6\tAP\t74, M\tNSCLC\tNivolumab\t201\t(-)\tPCI\tSurvived\t\n7\tAP\t79, M\tNSCLC\tNivolumab\t1102\t986\tNitrous acid\tSurvived\t\n8\tVSP\t58, M\tMelanoma\tPembrolizumab\t294\t204\tNitrous acid\tSurvived\t\n9\tPericardial effusion\t45, M\tNSCLC\tPembrolizumab\t59\t58\tPericardial drainage\tCancer death\t\n10\tPericardial effusion\t45, M\tNSCLC\tPembrolizumab\t253\t246\tPericardial drainage\tCancer death\t\n11\tPE\t77, F\tNSCLC\tPembrolizumab\t161\t(-)\tAnticoagulant therapy\tSurvived\t\n12\tHF\t71, M\tNSCLC\tNivolumab\t72\t(-)\tDiuretics\tCancer death\t\n13\tFulminant myocarditis\t59, M\tMelanoma\tIpilimumab\n\n → \n\nNivolumab\n\n\t495\t418\tMCS + PSL pulse\tSurvived from myocarditis, Cancer death\t\n14\tMyocardial vasculitis\t79, F\tMelanoma\tPembrolizumab\t263\t74\tPSL\tSurvived\t\nICI immune checkpoint inhibitor, Paf paroxysmal atrial fibrillation, AFL atrial flutter, PSVT paroxysmal supraventricular tachycardia, VT ventricular tachycardia, AP angina pectoris, VSP vasospastic angina, PE pulmonary embolism, HF heart failure, NSCLC non-small cell lung cancer, PCI percutaneous coronary intervention, MCS mechanical circulatory support, PSL prednisolone, Other abbreviations as in Table 1\n\nTable 4 Cardiovascular irAEs in patients with and without prior non-cardiovascular irAEs\n\n\tAll\n(n = 409)\tPrior non-cardiovascular\nirAEs ( +)\n(n = 133)\tPrior non-cardiovascular\nirAEs (-)\n(n = 276)\tP value\t\nCardiovascular irAEs\t14 (3.4)\t9 (6.8)\t5 (1.8)\t0.017\t\nAbbreviations as in Table 1\n\nKaplan–Meier survival curves for all-cause mortality\n\nThe median follow-up period was 278 (152–508) days. The comparison of the prognoses between patients who did and did not develop irAEs showed that the prognosis was significantly better for patients with irAEs than for patients without irAEs (P < 0.001) (Fig. 3). Furthermore, this tendency was detected in patients with (P < 0.001) and without a cardiovascular history (P < 0.001). The landmark analysis revealed that even after excluding patients who died within 3 months the prognosis was better for patients with irAEs than for those without irAEs regardless of their cardiovascular history (Supplemental Figure S1).Fig. 3 Kaplan–Meier survival analysis for all-cause mortality. The prognosis of patients with immune-related adverse events (irAEs) was significantly better than that of patients without irAEs (P < 0.001). This was also detected in patients with a cardiovascular history (P < 0.001) and in those without a cardiovascular history (P < 0.001)\n\nPredictors of all-cause mortality\n\nIn order to evaluate the prognostic impact of the occurrence of irAEs, we performed cox proportional hazard analysis (Table 5). The occurrence of an irAE and serum albumin level were independent predictors after adjusting for age, sex, body mass index, hemoglobin, C-reactive protein, hypertension, diabetes mellitus, dyslipidemia, and cardiovascular history (occurrence of irAE: HR 0.450, 95% CI 0.322–0.630, P < 0.001; serum albumin level: HR 0.438, 95% CI 0.308–0.623, P < 0.001) (Table 5). After excluding patients who died within 3 months, the occurrence of an irAE, serum albumin level were also independent predictors of all-cause mortality (Supplemental Table S1).Table 5 Cox proportional hazards regression analysis for all cause mortality, multivariate model\n\n\tHR\t95% CI\tP value\t\nAge, per 1 year\t0.997\t0.983–1.011\t0.66\t\nSex, female\t1.240\t0.894–1.721\t0.20\t\nBMI, per 1 kg/m2\t0.979\t0.942–1.019\t0.30\t\nAlbumin, per 1 g/dL\t0.438\t0.308–0.623\t < 0.001\t\nHemoglobin, per 1 g/dL\t1.061\t0.963–1.169\t0.23\t\nCRP, per 1 mg/dL\t1.012\t0.975–1.050\t0.53\t\nHypertension\t0.936\t0.678–1.292\t0.69\t\nDiabetes mellitus\t1.019\t0.698–1.487\t0.92\t\nDyslipidemia\t1.107\t0.733–1.672\t0.63\t\nCardiovascular history\t1.150\t0.756–1.643\t0.58\t\nIrAEs\t0.450\t0.322–0.630\t < 0.001\t\nHR hazard ratio, CI confidence interval, Other abbreviations as in Table 1\n\nDiscussion\n\nWe retrospectively analyzed 409 patients who received ICI therapy, and our results confirmed that patients with irAEs had a better prognosis than those without irAEs regardless of their cardiovascular history. Furthermore, cardiovascular irAEs, which require drug therapy and/or invasive treatment after ICI administration, occurred in 14 (3.4%) patients, and cardiovascular irAEs occurred more frequently in patients with prior non-cardiovascular irAEs. Our results demonstrated that irAEs over grade 2 was a stronger prognostic factor than cardiovascular history.\n\nIrAEs are pathologically characterized by macrophagic and lymphocytic infiltration into the normal tissues and result from the unintended effects of ICI-induced activation of the immune system. Since 2015, various studies have reported that irAEs are associated with a longer prognosis regardless of the treatment regimen [5, 6]. Shimozaki et al. reported that the development of multiple irAEs was associated with longer survivals than a single irAE [19]. Conversely, Naqash et al. reported the negative impact of irAE-related treatment discontinuation on survival [20]. Inhibition of PD-1, PD-L1 and CTLA-4 activates not only tumor-specific T cells but also autoimmunity, and tumor-specific neoplastic antigens and normal tissue antigens may be cross-reactive. These mechanisms may be related to the relation between the occurrence of irAEs and good clinical response, although the precise mechanism has not been fully uncovered [21].\n\nAlthough several previous reports have demonstrated the relationship between ICI therapy and adverse cardiovascular events [22, 23], no studies have examined the prognostic effects of the coexistence of cardiovascular disease. We speculated the following reasons for the positive impact of irAEs regardless of cardiovascular history: 1) most of cardiovascular comorbidities were stable conditions that more than one year had passed from the onset, and 82.6% of patients with cardiovascular history were followed by cardiologists or family physicians during ICI therapy, 2) fatal cardiovascular irAEs such as myocarditis are infrequent, and in this study, the myocarditis occurred during hospitalization, allowing for prompt therapeutic intervention, and 3) ICIs were used for cancers in which the primary lesion was unresectable and for recurrent or irreversible cancers; therefore, the prognosis of cancer itself was poor.\n\nSimilar to Liew et al., who reported that rheumatic irAEs were associated with other non-rheumatic irAEs [24], we found that non-cardiovascular irAEs may increase the incidence of cardiovascular irAEs. In underlying pathophysiology, the main hypothesized mechanism of ICI-induced cardiotoxicity (cardiovascular irAEs) is the extreme reaction of cytotoxic T-cells, which leads to the increased activity of inflammatory and non-inflammatory cytokines. This toxicity may involve any region in the heart, and cytokine storms directly damage the myocardium, pericardium, electrical circuit, endothelial cells, and coagulation function, leading to the destabilization of atherosclerotic lesions. The most representative cardiovascular irAE is myocarditis. Mahmood et al. reported a 1.14% prevalence of ICI-related myocarditis in a multicenter observational study, and fulminant myocarditis was noted in 0.17% of all patients [25]. The median time to onset of myocarditis post ICI administration has been reported as approximately 30 days in most studies [25, 26], although some have indicated that it can occur at any time [27, 28]. In fact, myocardial vasculitis and fulminant myocarditis developed 263 and 495 days after the first administration of ICIs, respectively [8, 29]. Furthermore, in both cases, grade 2 irAEs had been detected in other organs before those conditions occurred (Table 3). At times, it can be difficult to definitively diagnose cardiovascular irAEs, but it should be recognized that ICIs cause cardiovascular complications such as arrhythmia and acute coronary syndrome more frequently than previously reported.\n\nThe number of cancer patients who have survived because of rapid advances in treatment drugs has been increasing. In a double-blind, phase three, epoch-making trial of dual ICI therapy, 58% of advanced melanoma patients treated with nivolumab and ipilimumab combination therapy were still surviving at three years [30]. Because the number of patients receiving ICI treatment for long periods has been increasing, it is necessary to pay attention to possible cardiovascular disease. Furthermore, stably controlling cardiovascular comorbidities and preventing fatal cardiovascular events may improve prognoses in patients who have already developed irAEs in other organs.\n\nLimitations\n\nOur study has some limitations. First, this was a single-center study with a small number of patients, and there was no comparison group such as cancer patients without ICI therapy. Second, we obtained the information retrospectively from medical records, and we did not have a standardized system to perform routine examinations for all patients, such as electrocardiogram, echocardiography, or myocardial biomarkers before and after ICI administration; considering this we may not have investigated some cardiovascular disorders that did not cause major clinical problems. Third, because the follow-up protocol for patients with cardiovascular history was not standardized, we cannot deny the possibility that differences of follow-up affected the results. Fourth, although ICI discontinuation and post ICI therapy would affect prognosis, these factors could not be considered in the statistical analysis. Finally, although it is difficult to exclude the possibility that a longer prognosis increases the rate of irAEs, we statistically showed that irAEs remained an independent predictor.\n\nConclusions\n\nAlthough cardiovascular irAEs may be related to prior non-cardiovascular irAEs under ICI therapy, the occurrence of irAEs had a better prognostic impact and this tendency was not affected by cardiovascular history.\n\nSupplementary Information\n\nAdditional file 1: Supplemental Figure S1. Landmark analysis, excluding patients who died within 3 months. Kaplan–Meier survival analysis for all-cause mortality. The prognosis of patients with immune-related adverse events (irAEs) was significantly better than that of patients without irAEs (P < 0.001). This was also detected in patients with a cardiovascular history (P = 0.014) and in those without a cardiovascular history (P = 0.001).\n\nAdditional file 2: Supplemental Table S1. Cox proportional hazards regression analysis for all cause mortality, excluding patients who died within 3 months, multivariate model\n\nAbbreviations\n\nICI(s) Immune checkpoint inhibitor(s)\n\nirAE(s) Immune-related adverse event(s)\n\nPD-1 Programmed cell death-1\n\nPD-L1 Programmed death-ligand-1\n\nCTLA-4 Cytotoxic T-lymphocyte antigen-4\n\nASCO American Society of Clinical Oncology\n\nAcknowledgements\n\nNot applicable\n\nAuthors’ contributions\n\nSK, RM, KF, TS, YKB and YAndo contributed to the conception and design of this manuscript. SK, YK, NS, RO, TA, TMizutani, HO, YArao, TKuwayama, HH, TKondo and KF acquired data. SK, RM and TO performed statistical analyses, interpreted the data, and drafted the manuscript under supervision of senior authors TMurohara. All authors contributed to the conception, design, critical revision and final approval of this manuscript.\n\nFunding\n\nThere was no funding or financial support for this report.\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nWe obtained prior approval that the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki from the Ethics Committee of Nagoya University Hospital (approval number 2019–0176). There was no need for written consent or consent for publication.\n\nConsent for publication\n\nNot applicable.\n\nCompeting interests\n\nTO has received research grants from Ono Pharmaceutical Co., Ltd., Bayer Pharmaceutical Co., Ltd., Daiichi-Sankyo Pharma Inc., and Amgen Astellas BioPharma K.K. outside the submitted work. TO received honorariums from Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Novartis Pharma K. K., and Medtronic Japan Co., Ltd.\n\nYA received grants and personal fees from Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Nippon Kayaku Co., Yakult Honsha Co., Ltd., Eli Lilly Japan K.K., Mochida Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Ltd., Eisai Co., Ltd., personal fees from Novartis Pharma K.K., Bayer Holding Ltd., Bristol-Myers Squibb, Sawai Pharmaceutical Co., Ltd., Tsumura & Co., Otsuka Holdings Co., Ltd., Roche Pharmaceutical Industries Ltd., outside the submitted work.\n\nTM received lecture fees from Bayer Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Kowa Co., Ltd., MSD K. K., Mitsubishi Tanabe Pharma Co., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K. K., Pfizer Japan Inc., Sanofi-aventis K. K., and Takeda Pharmaceutical Co., Ltd. TM received unrestricted research grant for Department of Cardiology, Nagoya University Graduate School of Medicine from Astellas Pharma Inc., Daiichi-Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Kowa Co., Ltd., MSD K. K., Mitsubishi Tanabe Pharma Co., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K. K., Otsuka Pharma Ltd., Pfizer Japan Inc., Sanofi-aventis K. K., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd. The remaining authors have nothing to disclose.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Postow MA Callahan MK Wolchok JD Immune checkpoint blockade in cancer therapy J Clin Oncol 2015 33 17 1974 1982 10.1200/JCO.2014.59.4358 25605845\n2. Farkona S Diamandis EP Blasutig IM Cancer immunotherapy: the beginning of the end of cancer? BMC Med 2016 14 1 73 10.1186/s12916-016-0623-5 27151159\n3. Darnell EP Mooradian MJ Baruch EN Yilmaz M Reynolds KL Immune-related adverse events (irAEs): diagnosis, management, and clinical pearls Curr Oncol Rep 2020 22 4 39 10.1007/s11912-020-0897-9 32200442\n4. Matsuoka H Hayashi T Takigami K Correlation between immune-related adverse events and prognosis in patients with various cancers treated with anti PD-1 antibody BMC Cancer 2020 20 1 656 10.1186/s12885-020-07142-3 32664888\n5. Sanlorenzo M Vujic I Daud A Pembrolizumab cutaneous adverse events and their association with disease progression JAMA Dermatol 2015 151 11 1206 10.1001/jamadermatol.2015.1916 26222619\n6. Ando T Ueda A Ogawa K Prognosis of immune-related adverse events in patients with advanced sto cancer treated with nivolumab or pembrolizumab: a multicenter retrospective analysis Vivo 2021 35 1 475 482 10.21873/invivo.12281\n7. Boer RA Meijers WC Meer P Veldhuisen DJ Cancer and heart disease: associations and relations Eur J Heart Fail 2019 21 12 1515 1525 10.1002/ejhf.1539 31321851\n8. Yamaguchi S Morimoto R Okumura T Late-onset fulminant myocarditis with immune checkpoint inhibitor nivolumab Can J Cardiol 2018 34 6 812.e811 812.e813 10.1016/j.cjca.2018.03.007\n9. Johnson DB Balko JM Compton ML Fulminant myocarditis with combination immune checkpoint blockade N Engl J Med 2016 375 18 1749 1755 10.1056/NEJMoa1609214 27806233\n10. Khaddour K Singh V Shayuk M Acral vascular necrosis associated with immune-check point inhibitors: case report with literature review BMC Cancer 2019 19 1 449 10.1186/s12885-019-5661-x 31088420\n11. Comont T Sibaud V Mourey L Cougoul P Beyne-Rauzy O Immune checkpoint inhibitor-related acral vasculitis J Immunother Cancer 2018 6 1 120 10.1186/s40425-018-0443-6 30446009\n12. Yun S Vincelette ND Mansour I Hariri D Motamed S Late onset ipilimumab-induced pericarditis and pericardial effusion: a rare but life threatening complication Case Rep Oncol Med 2015 2015 794842 25918658\n13. De Almeida DVP Gomes JR Haddad FJ Buzaid AC Immune-mediated pericarditis with pericardial tamponade during nivolumab therapy J Immunother 2018 41 7 329 331 10.1097/CJI.0000000000000217 29461982\n14. Sharma M Suero-Abreu GA Kim B A case of acute heart failure due to immune checkpoint blocker nivolumab Cardiol Res 2019 10 2 120 123 10.14740/cr838 31019642\n15. Cautela J Rouby F Salem J-E Acute coronary syndrome with immune checkpoint inhibitors: a proof-of-concept case and pharmacovigilance analysis of a life-threatening adverse event Can J Cardiol 2020 36 4 476 481 10.1016/j.cjca.2019.11.035 32144037\n16. Wang DY Salem JE Cohen JV Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis JAMA Oncol 2018 4 12 1721 1728 10.1001/jamaoncol.2018.3923 30242316\n17. Grabie N Lichtman AH Padera R T cell checkpoint regulators in the heart Cardiovasc Res 2019 115 5 869 877 10.1093/cvr/cvz025 30721928\n18. Brahmer JR Lacchetti C Schneider BJ Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline J Clin Oncol 2018 36 17 1714 1768 10.1200/JCO.2017.77.6385 29442540\n19. Shimozaki K Sukawa Y Beppu N Multiple immune-related adverse events and anti-tumor efficacy: real-world data on various solid tumors Cancer Manag Res 2020 12 4585 4593 10.2147/CMAR.S247554 32606951\n20. Naqash AR Ricciuti B Owen DH Outcomes associated with immune-related adverse events in metastatic non-small cell lung cancer treated with nivolumab: a pooled exploratory analysis from a global cohort Cancer Immunol Immunother 2020 69 7 1177 1187 10.1007/s00262-020-02536-5 32140762\n21. Okada N Kawazoe H Takechi K Association between immune-related adverse events and clinical efficacy in patients with melanoma treated with nivolumab: a multicenter retrospective study Clin Ther 2019 41 1 59 67 10.1016/j.clinthera.2018.11.004 30528047\n22. Hu JR Florido R Lipson EJ Cardiovascular toxicities associated with immune checkpoint inhibitors Cardiovasc Res 2019 115 5 854 868 10.1093/cvr/cvz026 30715219\n23. Heinzerling L, Ott PA, Hodi FS, et al. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immuno Ther Cancer. 2016;4:50.\n24. Liew DFL Leung JLY Liu B Cebon J Frauman AG Buchanan RRC Association of good oncological response to therapy with the development of rheumatic immune-related adverse events following PD-1 inhibitor therapy Int J Rheum Dis 2019 22 2 297 302 10.1111/1756-185X.13444 30549256\n25. Mahmood SS Fradley MG Cohen JV Myocarditis in patients treated with immune checkpoint inhibitors J Am Coll Cardiol 2018 71 16 1755 1764 10.1016/j.jacc.2018.02.037 29567210\n26. Salem J-E Manouchehri A Moey M Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study Lancet Oncol 2018 19 12 1579 1589 10.1016/S1470-2045(18)30608-9 30442497\n27. Escudier M Cautela J Malissen N Clinical features, management, and outcomes of immune checkpoint inhibitor–related cardiotoxicity Circulation 2017 136 21 2085 2087 10.1161/CIRCULATIONAHA.117.030571 29158217\n28. Jain V Bahia J Mohebtash M Barac A Cardiovascular complications associated with novel cancer immunotherapies Curr Treat Options Cardiovasc Med 2017 19 5 36 10.1007/s11936-017-0532-8 28401456\n29. Oishi H Morimoto R Shimoyama Y Myocardial vasculitis associated with the immune checkpoint inhibitor pembrolizumab JACC: Case Rep 2020 2 12 1937 1941\n30. Wolchok JD Chiarion-Sileni V Gonzalez R Overall survival with combined nivolumab and ipilimumab in advanced melanoma N Engl J Med 2017 377 14 1345 1356 10.1056/NEJMoa1709684 28889792\n\n",
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"abstract": "A 45-year-old female with history of contact lens wear presented with a persistent corneal ulcer that was unresponsive to topical moxifloxacin. The patient's exam was concerning for fungal keratitis. Cultures were obtained, and the patient was started on fortified amphotericin B drops and oral voriconazole. The cultures identified Candida dubliniensis as the causative organism. The patient's exam worsened despite treatment, and the decision was made for surgery. At the time of surgery, her cornea was found to have unexpectedly perforated. She underwent cryotherapy; tectonic penetrating keratoplasty; anterior chamber tap; intracameral voriconazole, amphotericin B, and cefuroxime; and a partial conjunctival flap. Pathology from the cornea showed GMS and PAS stains positive for fungal forms. C. dubliniensis is a yeast closely related to Candida albicans that was first described in 1995 as a cause of oral candidiasis in patients with AIDS. There are a few published cases of endophthalmitis due to C. dubliniensis in the ophthalmology literature, but to our knowledge, no cases of fungal keratitis due to this organism have been reported. C. dubliniensis is a novel cause of fungal keratitis that can be difficult to identify and treat but is felt to be less virulent than C. albicans and generally susceptible to available anti-fungal therapies.",
"affiliations": "Havener Eye Institute, Department of Ophthalmology, The Ohio State University Wexner Medical Center, 915 Olentangy River Road, Columbus, Ohio 43212, USA.;Department of Pathology, The Ohio State University Wexner Medical Center, 410 W 10th Avenue, Columbus, Ohio 43210, USA.;Havener Eye Institute, Department of Ophthalmology, The Ohio State University Wexner Medical Center, 915 Olentangy River Road, Columbus, Ohio 43212, USA.",
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"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(18)30044-110.1016/j.idcr.2018.e00440e00440ArticleCandida dubliniensis: A novel cause of fungal keratitis Oostra Tyler D. Oostra.2@osu.edua⁎Schoenfield Lynn R. bMauger Thomas F. aa Havener Eye Institute, Department of Ophthalmology, The Ohio State University Wexner Medical Center, 915 Olentangy River Road, Columbus, Ohio 43212, USAb Department of Pathology, The Ohio State University Wexner Medical Center, 410 W 10th Avenue, Columbus, Ohio 43210, USA⁎ Corresponding author. Oostra.2@osu.edu14 8 2018 2018 14 8 2018 14 e00440 e00440 27 3 2018 11 8 2018 11 8 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 45-year-old female with history of contact lens wear presented with a persistent corneal ulcer that was unresponsive to topical moxifloxacin. The patient’s exam was concerning for fungal keratitis. Cultures were obtained, and the patient was started on fortified amphotericin B drops and oral voriconazole. The cultures identified Candida dubliniensis as the causative organism. The patient’s exam worsened despite treatment, and the decision was made for surgery. At the time of surgery, her cornea was found to have unexpectedly perforated. She underwent cryotherapy; tectonic penetrating keratoplasty; anterior chamber tap; intracameral voriconazole, amphotericin B, and cefuroxime; and a partial conjunctival flap. Pathology from the cornea showed GMS and PAS stains positive for fungal forms.\n\nC. dubliniensis is a yeast closely related to Candida albicans that was first described in 1995 as a cause of oral candidiasis in patients with AIDS. There are a few published cases of endophthalmitis due to C. dubliniensis in the ophthalmology literature, but to our knowledge, no cases of fungal keratitis due to this organism have been reported. C. dubliniensis is a novel cause of fungal keratitis that can be difficult to identify and treat but is felt to be less virulent than C. albicans and generally susceptible to available anti-fungal therapies.\n\nKeywords\nCandida dubliniensisFungal keratitisCorneal ulcer\n==== Body\nIntroduction\nCandida albicans has long been recognized as a cause of ocular infections including fungal keratitis. In recent years, newer related Candida species have also been identified as unique causes of ocular infection [1]. The purpose of this case report is to describe a case of infectious keratitis due to Candida dubliniensis. This organism has been described most frequently in the ophthalmologic literature as a cause of endophthalmitis [[2], [3], [4], [5], [6], [7]], but this is the first reported case of fungal keratitis to our knowledge.\n\nCase presentation\nA 45-year-old female with history of soft contact lens wear presented with eye pain, redness, and decreased vision for 2 months and a persistent corneal ulcer that was unresponsive to topical moxifloxacin. She was referred to our institution for further management of her recalcitrant corneal ulcer. At presentation, her vision was hand motion. Her external exam showed reactive ptosis. She had diffuse conjunctival injection and a round 2.0 mm fluffy white corneal infiltrate nasally with an overlying epithelial defect as well as surrounding microcystic edema and stromal haze. Her anterior chamber had 2+ cells with a layered 2.4 mm hypopyon. It was felt that the patient’s exam was concerning for fungal keratitis. Accordingly, bacterial and fungal cultures were obtained, and the patient was started on fortified amphotericin B drops and oral voriconazole. The cultures identified C. dubliniensis as the causative organism.\n\nThe patient’s exam worsened despite treatment, and the decision was made to take the patient to surgery for cryotherapy, intracameral anti-fungals, and a partial conjunctival flap. At the time of surgery, her cornea was found to have unexpectedly perforated after overlying mucus and necrotic debris were removed. Accordingly, she underwent cryotherapy; tectonic penetrating keratoplasty with VisionGraft gamma-irradiated human cornea; anterior chamber tap; intracameral voriconazole, amphotericin B, and cefuroxime; and a partial conjunctival flap (Fig. 1). At the time of surgery, the corneal tissue was submitted to pathology which showed necrotizing keratitis as well as GMS and PAS stains positive for fungal forms (Fig. 2, Fig. 3).Fig. 1 Post-operative external photo showing the patient’s nasal conjunctival flap with underlying tectonic patch graft.\n\nFig. 1Fig. 2 Pathology from the patient’s cornea demonstrating necrotizing keratitis and neutrophilic infiltrates (hematoxylin and eosin, 40X).\n\nFig. 2Fig. 3 Gomori methenamine silver (GMS) stain showing fungal pseudohyphae (400X).\n\nFig. 3\n\nShe did well post-operatively with improvement in her symptoms and exam. The conjunctival flap started to retract by the post-operative week one visit and was fully retracted by the post-operative month two visit. Her vision ultimately improved to 20/40 uncorrected, and she refracted to 20/30.\n\nDiscussion\nC. dubliniensis is a yeast closely related to Candida albicans that was first described in 1995 as a cause of oral candidiasis in patients with AIDS [8]. However, it has likely been around much longer and can be easily misidentified as C. albicans. In fact, one retrospective review found C. dubliniensis in fungal stock collections going back to the 1970s where it had been misidentified as C. albicans [9]. Accordingly, while this may be the first case where C. dubliniensis was specifically identified as the causative organism, it is quite possible that other cases of fungal keratitis due to C. dubliniensis have existed previously that were simply misidentified as C. albicans.\n\nWhile very similar to C. albicans, C. dubliniensis has been shown to be less virulent in both in vitro and in vivo studies [10,11]. This is likely due to the fact that it has a decreased ability to produce hyphae, is more susceptible to environmental stressors, and generates a more substantial early neutrophil response compared to C. albicans [10,11]. Chen et. al. in their study of the role of calcineurin in C. dubliniensis virulence actually created a mouse model of fungal keratitis where they demonstrated that C. albicans could cause infection in immunocompetent mouse corneas while C. dubliniensis could not and could only cause infection in the corneas of immunocompromised mice [12]. This is further supported by case series of endogenous endophthalmitis where visual outcomes have been shown to be better with C. dubliniensis as compared to C. albicans [5].\n\nIn the ophthalmology literature, C. dubliniensis was first described as a cause of fungal dacryocystitis [13] but has more recently been described as an emerging cause of endophthalmitis [[2], [3], [4], [5], [6], [7]]. It has specifically been linked to several cases of endogenous endophthalmitis in IV drug users [[3], [4], [5], [6]]. In fact, one such case was recently identified and treated at our institution by our retina colleagues.\n\nStudies of C. dubliniensis susceptibility have demonstrated emerging fluconazole resistance but nearly all reported isolates have shown susceptibility to amphotericin B and voriconazole [11,14]. Our patient, however, did not initially respond to topical amphotericin B and oral voriconazole but did ultimately do well with intracameral amphotericin B and voriconazole at the time of surgery as well as continued topical amphotericin B and oral voriconazole post-operatively.\n\nIn conclusion, C. dubliniensis is a novel cause of fungal keratitis that can be difficult to identify and treat but is fortunately likely less virulent than C. albicans and generally susceptible to available anti-fungal therapies.\n\nCRediT author statement\nTyler Oostra: Conceptualization, Investigation, Writing - Original Draft. Lynn Schoenfield: Writing - Reviewing and Editing. Thomas Mauger: Conceptualization, Writing - Reviewing and Editing, Supervision.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nConflict of interest statement\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1 Motukupally S.R. Nanapur V.R. Chathoth K.N. Murthy S.I. Pappuru R.R. Mallick A. Ocular infections caused by Candida species: type of species, in vitro susceptibility and treatment outcome Indian J Med Microbiol 33 4) October-December 2015 538 546 26470961 \n2 Sedeek R.W. Shah M. Gentile R. Samson C.M. First case report of Candida dubliniensis endogenous endophthalmitis Invest Ophthalmol Vis Sci 49 May 2008 952 \n3 Pelegrín L. Mesquida M. Adán A. Cervera C. Bosch-Mestres J. Esteban-Redondo Candida dubliniensis endophthalmitis in a HIV-infected intravenous drug abuser Mycoses 54 6) November 2011 e856 8 21929732 \n4 Espinosa-Heidmann D.G. McMillan B.D. Lasala P.R. Stanley J. Larzo C.R. Candida dubliniensis endophthalmitis: first case in North America Int Ophthalmol 32 1) Febuary 2012 41 45 22222717 \n5 Moloney T.P. Park J. Candida dubliniensis endophthalmitis: five cases over 15 years J Ophthalmic Inflamm Infect 3 1) November 2013 66 24252588 \n6 Rosenberger E. Youssef D.A. Safdar S. Larzo C.R. Myers J. Third case of Candida dubliniensis endogenous endophthalmitis in North America: case report and review of the literature Int Ophthalmol 34 4) August 2014 945 950 24234425 \n7 McMillan B.D. Miller G.J. Nguyen J. Rare case of exogenous Candida dubliniensis endophthalmitis: a case report and brief review of the literature J Ophthalmic Inflamm Infect 4 May 2014 11 24860628 \n8 Sullivan D.J. Westerneng T.J. Haynes K.A. Bennett D.E. Coleman D.C. Candida dubliniensis sp. nov.: phenotypic and molecular characterization of a novel species associated with oral candidosis in HIV-infected individuals Microbiology 141 Pt 7) July 1995 1507 1521 7551019 \n9 Odds F.C. Van Nuffel L. Dams G. Prevalence of Candida dubliniensis isolates in a yeast stock collection J Clin Microbiol 36 10) October 1998 2869 2873 9738035 \n10 Sullivan D. Coleman D. Candida dubliniensis: characteristics and identification J Clin Microbiol 36 2) Febuary 1998 329 334 9466736 \n11 Sullivan D.J. Moran J.P. Pinjon E. Al-Mosaid A. Stokes C. Vaughan C. Comparison of the epidemiology, drug resistance mechanisms, and virulence of Candida dubliniensis and Candida albicans FEMS Yeast Res 4 4-5) January 2004 369 376 14734017 \n12 Chen Y.L. Brand A. Morrison E.L. Silao F.G. Bigol U.G. Malbas F.F. Jr Calcineurin controls drug tolerance, hyphal growth, and virulence in Candida dubliniensis Eukaryot Cell 10 6) June 2011 803 819 21531874 \n13 Obi E. Roy A. Bates V. Sandy C. Bilateral chronic fungal dacryocystitis caused by Candida dubliniensis in a neutropenic patient J Clin Pathol 59 11) November 2006 1194 1195 17071804 \n14 Sebti A. Kiehn T.E. Perlin D. Chaturvedi V. Wong M. Doney A. Candida dubliniensis at a cancer center Clin Infect Dis 32 7) April 2001 1034 1038 11264031\n\n",
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"abstract": "OBJECTIVE\nThe aim of the present case report was to describe a novel pharmacokinetic drug–drug interaction between the antiplatelet agent clopidogrel and the antineoplastic agent paclitaxel.\n\n\nMETHODS\nThe patient was identified in a previously described cohort of 93 patients with ovarian carcinoma treated with paclitaxel. The effect of clopidogrel acyl-β-D-glucuronide on the metabolism of paclitaxel was assessed in human liver microsomes. The analysis of clopidogrel in plasma and the quantification of paclitaxel and 6-hydroxypaclitaxel in in vitro samples were performed by liquid chromatography tandem mass spectrometry.\n\n\nRESULTS\nThe patient was a 60-year-old female treated with an unknown dose of clopidogrel at the time of paclitaxel therapy. Clopidogrel was present in all three of the plasma samples obtained during paclitaxel dosing. Estimated unbound paclitaxel clearance was 238 l h−1, which was only 62% of the cohort geometric mean (385 l h−1; range 176–726). She was hospitalized three times, developed severe neuropathy and paclitaxel treatment was subsequently discontinued. In vitro, 30-min preincubation with 100 μM clopidogrel acyl-β-D-glucuronide inhibited the depletion rate of 0.5 μM paclitaxel by 51% and the formation rate of 6-hydroxypaclitaxel by 77%.\n\n\nCONCLUSIONS\nThis is the first report of a clopidogrel–paclitaxel interaction, suggesting that clinically used doses of clopidogrel can reduce the cytochrome P450 2C8 (CYP2C8)-mediated systemic clearance of paclitaxel, leading to an increased risk of paclitaxel toxicity. Caution should be exercised whenever the simultaneous use of paclitaxel and clopidogrel cannot be avoided.",
"affiliations": null,
"authors": "Bergmann|Troels K|TK|;Filppula|Anne M|AM|;Launiainen|Terhi|T|;Nielsen|Flemming|F|;Backman|Janne T|J|;Brosen|Kim|K|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D065687:Cytochrome P-450 CYP2C8 Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D013988:Ticlopidine; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.12795",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "81(2)",
"journal": "British journal of clinical pharmacology",
"keywords": null,
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000972:Antineoplastic Agents, Phytogenic; D001189:Aryl Hydrocarbon Hydroxylases; D000077144:Clopidogrel; D065727:Cytochrome P-450 CYP2C8; D065687:Cytochrome P-450 CYP2C8 Inhibitors; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008875:Middle Aged; D020258:Neurotoxicity Syndromes; D010051:Ovarian Neoplasms; D017239:Paclitaxel; D013988:Ticlopidine",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "313-5",
"pmc": null,
"pmid": "26446447",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21955855;25115434;7913410;24971633;16000582;20368717;7923194;26446447",
"title": "Neurotoxicity and low paclitaxel clearance associated with concomitant clopidogrel therapy in a 60-year-old Caucasian woman with ovarian carcinoma.",
"title_normalized": "neurotoxicity and low paclitaxel clearance associated with concomitant clopidogrel therapy in a 60 year old caucasian woman with ovarian carcinoma"
} | [
{
"companynumb": "DK-SA-2015SA162398",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SALICYLIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "RTOG 0839 is a Phase II study of pre-operative chemoradiotherapy with or without panitumumab in potentially operable locally advanced non-small cell lung cancer (NSCLC). The investigational agent, panitumumab, is an anti-epithelial growth factor receptor (EGFR) antibody that improves progression-free survival in chemorefractory metastatic colorectal cancer (mCRC). Recently, both KRAS mutational status (i.e., mutated or not) and subtype (i.e., activating or inactivating) have been shown to be predictive of response to anti-EGFR therapy in mCRC. However, in NSCLC, it is unknown if KRAS mutational status or subtype predict benefit to anti-EGFR therapies because of unique genetic and epigenetic factors unique to each cancer. We present a patient with stage III NSCLC containing a KRAS G12D activating mutation who had a partial pathologic response, with disappearance of a minor KRAS mutant clone. This case suggests possible eradication of the G12D KRAS lung cancer clones by concurrent chemoradiation with panitumumab.",
"affiliations": "Department of Radiation Oncology; Fox Chase Cancer Center; Philadelphia, PA USA.",
"authors": "Zaorsky|Nicholas G|NG|;Sun|Yunguang|Y|;Wang|Zixuan|Z|;Palmer|Joshua|J|;Fortina|Paolo M|PM|;Solomides|Charalambos|C|;Werner-Wasik|Maria|M|;Dicker|Adam P|AP|;Axelrod|Rita|R|;Campling|Barbara|B|;Evans|Nathaniel|N|;Cowan|Scott|S|;Lu|Bo|B|",
"chemical_list": "D000911:Antibodies, Monoclonal; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; D016190:Carboplatin; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.4161/cbt.25942",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-4047",
"issue": "14(10)",
"journal": "Cancer biology & therapy",
"keywords": "EGFR; KRAS; biomarker; non-small cell lung cancer; panitumumab",
"medline_ta": "Cancer Biol Ther",
"mesh_terms": "D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D001483:Base Sequence; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D059248:Chemoradiotherapy; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008875:Middle Aged; D020125:Mutation, Missense; D017239:Paclitaxel; D000077544:Panitumumab; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D011859:Radiography; D016896:Treatment Outcome; D018631:ras Proteins",
"nlm_unique_id": "101137842",
"other_id": null,
"pages": "883-7",
"pmc": null,
"pmid": "23917487",
"pubdate": "2013-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15519853;16724053;23630215;16618717;21737547;19482958;20921461;28629896;22974781;16467544;22734028;22712795;23401440;20680106;22722843;18316791;20038723;17785764;22397650;21985943;21555681;23122493;23407898;19029981",
"title": "Identification of a KRAS mutation in a patient with non-small cell lung cancer treated with chemoradiotherapy and panitumumab.",
"title_normalized": "identification of a kras mutation in a patient with non small cell lung cancer treated with chemoradiotherapy and panitumumab"
} | [
{
"companynumb": "US-AMGEN-USASP2020162251",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Metronidazole-induced neuro-toxicity, though rare, is known. A characteristic spatial distribution of lesions in cerebellar dentate nuclei and dorsal pons is known. However, temporal progression of lesions on magnetic resonance imaging (MRI) has not been described previously. We describe two such cases which presented initially with splenial hyperintesity and showed progression to characterstic lesions. Both cases improved with stoppage of metronidazole.",
"affiliations": "Department of Neuroradiology, Sri Bala Ji Action Medical Institute, New Delhi, India.;Department of Gynaecology, Kasturba Hospital, New Delhi, India.;Department of Neurology, Sri Bala Ji Action Medical Institute, New Delhi, India.;Department of Neurology, Sri Bala Ji Action Medical Institute, New Delhi, India.",
"authors": "Singh|Rupinder|R|;Kaur|Ramanjeet|R|;Pokhariyal|Pawan|P|;Aggarwal|Rajul|R|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.4103/ijri.IJRI_341_16",
"fulltext": "\n==== Front\nIndian J Radiol ImagingIndian J Radiol ImagingIJRIThe Indian Journal of Radiology & Imaging0971-30261998-3808Medknow Publications & Media Pvt Ltd India IJRI-27-12910.4103/ijri.IJRI_341_16NeuroradiologySequential MR imaging (with diffusion-weighted imaging) changes in metronidazole-induced encephalopathy Singh Rupinder Kaur Ramanjeet 2Pokhariyal Pawan 1Aggarwal Rajul 1Department of Neuroradiology, Sri Bala Ji Action Medical Institute, New Delhi, India1 Department of Neurology, Sri Bala Ji Action Medical Institute, New Delhi, India2 Department of Gynaecology, Kasturba Hospital, New Delhi, IndiaCorrespondence: Dr. Rupinder Singh, Department of Neuroradiology, Sri Bala Ji Action Medical Institute, New Delhi, India. E-mail: rupinder.dr@gmail.comApr-Jun 2017 27 2 129 132 Copyright: © 2017 Indian Journal of Radiology and Imaging2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Metronidazole-induced neuro-toxicity, though rare, is known. A characteristic spatial distribution of lesions in cerebellar dentate nuclei and dorsal pons is known. However, temporal progression of lesions on magnetic resonance imaging (MRI) has not been described previously. We describe two such cases which presented initially with splenial hyperintesity and showed progression to characterstic lesions. Both cases improved with stoppage of metronidazole.\n\nMagnetic resonance imagingmetronidazolemetronidazole-induced encephalopathysplenial hyperintensity\n==== Body\nIntroduction\nMetronidazole is an antibiotic, antiprotozoal, and amoebicide agent of the nitroimidazole group. It is one of the commonly used antibiotics in clinical practice and is considered safe. In the past few years, there have been few reports of metronidazole-induced neurotoxicity and characteristic pattern of bilateral symmetrical hyperintensity in the supratentorial white matter, corpus callosum, and within the cerebellum and deep cerebellar nuclei on magnetic resonance imaging (MRI).[1] However, none of these describe the temporal progression of lesions on MRI. We present two cases depicting progressive MRI changes including diffusion-weighted imaging (DWI) changes of metronidazole toxicity.\n\nCase History\nCase 1\nA 41-year-old male presented with fever for 2 days, slurring of speech, difficulty in recognition, and irrelevant talk since 1 day. No history of headache, loss of consciousness, or seizures was present. Patient was admitted 15 days back with complaints of loose motions, abdominal pain, and fever. He was diagnosed to have amoebic liver abscess and was started on metronidazole 400 mg orally thrice a day.\n\nThis time neurological examination revealed altered consciousness [Glasgow Coma Scale 14 (E4M6V4)], disorientation, bilateral reacting pupils, slurring of speech, and positive cerebellar signs with left past pointing. No cranial nerve palsy or motor weakness was seen.\n\nMRI brain on day 1 of the admission showed DWI hyperintensity in the splenium of corpus callosum suggesting acute infarct or toxic encephalopathy. Restricted diffusion was confirmed on apparent diffusion coefficient mapping (with ADC value of 0.5 × 10-3 mm2/s) [Figure 1]. Gradient recovery echo images showed no evidence of hemorrhage.\n\nFigure 1(A-D) Initial Magnetic resonance imaging (Brain) of case 1, showing symmetric areas of hyper intensity in splenium of the corpus callosum (arrow) on DWI (A) with restricted diffusion ADC mapping (B) (ADC value of 0.5 × 10-3 mm2/s) and T2-weighted images, axial (C and D) no signal change in corpus callosum (C) cerebellum and pons (D)\n\nThe patient was started on antiplatelet, low molecular weight heparin, and other supportive treatment. Metronidazole was continued. However, there was no improvement, rather severity of ataxia increased.\n\nMRI brain repeated on the fifth day showed hyperintensities involving the bilateral dentate nuclei in cerebellum with resolution of corpus callosal lesions suggesting toxic encephalopathy [Figure 2].\n\nFigure 2(A-D) Follow up MRI of case 1 after 5 days, showing resolution of hyper intensity in splenium of corpus callosum (arrow) on DWI (A) normal signal on T2W (B) and characteristic involvement of dentate nucleus on (C) Axial FLAIR and (D) Axial T2-weighted images\n\nAt this point, metronidazole toxicity was strongly considered. Metronidazole was immediately stopped, and the patient started showing recovery over next 3 days. He was discharged on the eighth day without any motor or cranial nerve deficit.\n\nCase 2\nA 56-year-old female presented with difficulty in speech and decreased hearing since 1 day. She was taking metronidazole 400 mg orally thrice daily since 5 days for gastroenteritis (severe vomiting and loose motions). The patient was admitted with a possibility of cerebrovascular event and investigated.\n\nHer neurological examination revealed disorientation, altered consciousness (GCS-E4M5Vslurred), bilateral reacting pupils, slurring of speech, and positive cerebellar signs with right cerebellar ataxia. Motor examination revealed right upper limb weakness with power of 4/5 and bilateral mute plantar reflexes.\n\nMRI brain [Figure 3] which showed hyperintensity in the splenium of corpus callosum with diffusion restriction (ADC value of 0.6 × 10-3 mm2/s) for which radiological possibilities of infarct, metabolic, or viral encephalitis were considered. Lumbar puncture showed 3 cells, mostly lymphocytes, glucose 80mg/dl, and protein 20mg/dl.\n\nFigure 3(A-D) Initial Magnetic resonance imaging (Brain) of case 2, showing symmetric areas of hyper intensity involving the splenium of the corpus callosum (arrow) on (A) Axial DWI with restricted diffusion (value of 0.6 × 10-3 mm2/s) on ADC map (B), (C) axial T2-weighted images, signal change in corpus callosum (D) Axial DWI no signal change in cerebellum and pons\n\nShe was started with antiplatelets, antibiotics, and other supportive treatment. Metronidazole was continued. Patient condition deteriorated over the next 48 hours, became drowsier, and was intubated. MRI brain [Figure 4] repeated after 3 days showed multiple hyperintense lesions in corpus callosum, dentate nuclei of cerebellum, brainstem, and deep white matter, suggesting toxic encephalopathy.\n\nFigure 4(A-D) Follow up MRI brain, Axial T2 (A-C) Multiple T2 hyper intense lesions at characteristic sites involving corpus callosum (bold arrow), subcortical white matter (arrow), midbrain (B), dentate nucleus (arrowhead) and dorsal pons. (D) Axial DWI showing symmetric areas of hyper intensity involving the splenium of the corpus callosum\n\nPossibility of metronidazole toxicity was strongly considered at this stage. Metronidazole was withheld immediately. Patient started improving and was weaned off the ventilator over the next 3 days. Patient was discharged on the ninth day in stable condition.\n\nDiscussion\nThe available literature describes very few cases with imaging findings of metronidazole-induced encephalopathy and none describe the temporal progression of initial midline splenial lesions to more characteristic sites as bilateral symmetrical supratentorial white matter and deep cerebellar nuclei, as seen in both our cases.\n\nAmong the initial descriptions in literature, Ahmed et al.[1] were the first to describe MRI findings of metronidazole toxicity in a 45-year-old female as bilateral symmetrical, abnormal hyperintensity in the supratentorial white matter, corpus callosum, and within the cerebellum and deep cerebellar nuclei on T2-weighted images. They suggested axonal swelling with increased water content due to toxic injury or localized reversible ischemia due to vascular spasm as possible mechanism. A few subsequent case reports[234] have described symmetric lesions at additional sites as in colliculus, superior olive, and cochlear nuclei, indicating their reversibility. Other theories for signal changes including interstitial edema and ischemia as cause of signal intensity on diffusion-weighted imaging or cell damage to Purkinje cells due to binding of the drug to neuronal RNA, causing inhibition of protein synthesis, and axonal degeneration have also been postulated.[234]\n\nSecond MR in our cases showed similar characteristic spatial distribution of cerebellar dentate nuclei and dorsal pons in both the cases prompting us to implicate metronidazole as a causative agent. Other common causes of such multifocal hyper intensities such as multiple sclerosis, acute disseminated encephalomyelitis, Wernicke encephalopathy, and enteroviral encephalomyelitis were excluded by clinical history and investigations.\n\nIn both our cases, initial imaging showed only splenial hyperintensity on DWI. The differential diagnosis of splenial hyperintensity (or boomerang sign as it is sometimes described)[5] is vast including ischemia, infections – encephalitis (influenza, Escherichia coli, mumps, adenovirus, Epstein-Barr, virus and Rota virus), demyelinating lesions including multiple sclerosis, posterior reversible encephalopathy syndrome, diffuse axonal injury, Marchiafava-Bignami disease, adrenoleukodystrophy, AIDS dementia complex, lymphoma, epilepsy, antiepileptic drug usage, osmotic myelinolysis, and acute toxic encephalopathy.[6] However, mechanism of this splenial hyperintensity is incompletely understood. Various mechanisms proposed include breakdown of the blood–brain barrier,[7] reversible demyelination or transient disturbance of energy metabolism, and ionic transport causing intramyelinic edema.[8] In both the cases, metronidazole toxicity was not considered at the onset, and the drug was continued as index of suspicion was low both radiologically and clinically. Both these cases showed restricted diffusion on initial MR indicative of cytotoxic edema as cause in initial stage, suggesting a mechanism of intramyelinic edema.\n\nWe propose a mechanism of selective vulnerability and variable affinity of neurons for metronidazole as cause of characteristic and temporal progression of lesions. Metronidazole or its immune mediator may have specific high affinities receptors on splenial axons evidenced by initial cytotoxic edema (confirmed by high ADC values), and persistent exposure might result in cell damage and involvement of other characteristic sites with lesser affinity such as cerebellar dentate nuclei dorsal pons and cerebral white matter.\n\nThese cases call attention to metronidazole toxicity as differential diagnosis of splenial hyperintensity before MRI reveals characteristic multifocal site pattern.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflict of interest.\n==== Refs\n1 Ahmed A Loes DJ Bressler EL Reversible magnetic resonance imaging findings in metronidazole induced encephalopahty Neurology 1995 45 588 9 7898724 \n2 Kim E Na DG Kim EY Kim JH Son KR Chang KH Imaging of metronidazole induced encephalopathy: Lesion distribution and diffusion-weighted imaging findings Am J Neuroradiol 2007 28 1652 8 17885234 \n3 Lee SS Cha SH Lee SY Song CJ Reversible inferior colliculus lesion in metronidazole induced encephalopathy: Magnetic resonance findings on diffusion-weighted and Fluid Attenuated Inversion Recovery Imaging J Comput Assist Tomogr 2009 33 305 8 19346865 \n4 Kalia V Vibhuti Saggar K Case report: MRI of the brain in metronidazole toxicity Indian J Radiol Imaging 2010 20 195 7 21042443 \n5 Hardeep M S Ravindra GK Mukund VR Pawan KS Boomerang sign: Clinical significance of transient lesion in splenium of corpus callosum Ann Indian Acad Neurol 2012 15 151 7 22566735 \n6 Conti M Salis A Urigo C Canalis L Frau S Canalis GC Transient focal lesion in the splenium of the corpus callosum: MR imaging with an attempt to clinical-physiopathological explanation and review of the literature Radiol Med 2007 112 921 35 17885738 \n7 Cohen-Gadol AA Britton JW Jack CR Jr Friedman JA Marsh WR Transient postictal magnetic resonance imaging abnormality of the corpus callosum in a patient with epilepsy. Case report and review of the literature J Neurosurg 2002 97 714 7 12296661 \n8 Oster J Doherty C Grant PE Simon M Cole AJ Diffusion-weighted imaging abnormalities in the splenium after seizures Epilepsia 2003 44 852 4 12790901\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0970-2016",
"issue": "27(2)",
"journal": "The Indian journal of radiology & imaging",
"keywords": "Magnetic resonance imaging; metronidazole; metronidazole-induced encephalopathy; splenial hyperintensity",
"medline_ta": "Indian J Radiol Imaging",
"mesh_terms": null,
"nlm_unique_id": "8503873",
"other_id": null,
"pages": "129-132",
"pmc": null,
"pmid": "28744071",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "7898724;22566735;17885234;19346865;17885738;21042443;12296661;12790901",
"title": "Sequential MR imaging (with diffusion-weighted imaging) changes in metronidazole-induced encephalopathy.",
"title_normalized": "sequential mr imaging with diffusion weighted imaging changes in metronidazole induced encephalopathy"
} | [
{
"companynumb": "IN-BAUSCH-BL-2017-022151",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nEsophageal small-cell cancer is a rare disease, and standard therapy has not yet been established.\n\n\nMETHODS\nA total of 12 esophageal small-cell carcinoma patients were treated with CPT-11 (70 mg/m(2)) on Days 1 and 15 and CPT-11 plus CDDP (80 mg/m(2)) on Day 1 with each cycle repeated every 4 weeks at our institution.\n\n\nRESULTS\nA total of 46 chemotherapy courses were given (median, 3.5). There were two complete responses and eight partial responses. The median survival time was 417 (97-1626) days, and three patients were still alive for >40 months. Grade 4 neutropenia was observed in two patients, Grade 4 anemia in one patient, Grade 3-4 diarrhea in three patients and Grade 3-4 hyponatremia in three patients. Other adverse reactions seen were mild with no treatment-related deaths observed.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first report of the series of more than 10 patients with small-cell carcinoma of the esophagus treated with the same chemotherapy regimen. The combination of CPT-11 and CDDP appears to be effective therapy of this disease with acceptable toxicity profile. We believe that this regimen is one of the options to be considered for treatment of esophageal small-cell carcinoma.",
"affiliations": "Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan. kchin@jfcr.or.jp",
"authors": "Chin|Keisho|K|;Baba|Satoshi|S|;Hosaka|Hisashi|H|;Ishiyama|Akiyoshi|A|;Mizunuma|Nobuyuki|N|;Shinozaki|Eiji|E|;Suenaga|Mitsukuni|M|;Kozuka|Takuyo|T|;Seto|Yasuyuki|Y|;Yamamoto|Noriko|N|;Hatake|Kiyohiko|K|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002945:Cisplatin; D002166:Camptothecin",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyn041",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "38(6)",
"journal": "Japanese journal of clinical oncology",
"keywords": null,
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000368:Aged; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D018288:Carcinoma, Small Cell; D002945:Cisplatin; D004938:Esophageal Neoplasms; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "426-31",
"pmc": null,
"pmid": "18519543",
"pubdate": "2008-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Irinotecan plus cisplatin for therapy of small-cell carcinoma of the esophagus: report of 12 cases from single institution experience.",
"title_normalized": "irinotecan plus cisplatin for therapy of small cell carcinoma of the esophagus report of 12 cases from single institution experience"
} | [
{
"companynumb": "JP-CIPLA LTD.-2014JP02188",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA's MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner.",
"affiliations": null,
"authors": "Mancano|Michael A|MA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1310/hpj5108-623",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-5787",
"issue": "51(8)",
"journal": "Hospital pharmacy",
"keywords": null,
"medline_ta": "Hosp Pharm",
"mesh_terms": null,
"nlm_unique_id": "0043175",
"other_id": null,
"pages": "623-627",
"pmc": null,
"pmid": "27698499",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ipilimumab-Induced Polyneuropathy; Ibuprofen-Induced Allergic-Type Liver Injury; Trimethoprim-Sulfamethoxazole-Induced Immune Thrombocytopenia in Children; Mesna-Induced Fixed Drug Eruption; Digoxin-Induced Ocular Toxicity.",
"title_normalized": "ipilimumab induced polyneuropathy ibuprofen induced allergic type liver injury trimethoprim sulfamethoxazole induced immune thrombocytopenia in children mesna induced fixed drug eruption digoxin induced ocular toxicity"
} | [
{
"companynumb": "US-BION-005773",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "1",
"drugadmi... |
{
"abstract": "OBJECTIVE\nTo retrospectively assess and analyze the clinical efficacy and safety of off-label interleukin-1 (IL-1) blockade with anakinra during pregnancy of patients with familial Mediterranean fever (FMF).\n\n\nMETHODS\nRetrospective analysis of clinical and laboratory parameters making use of an electronic database system. Detailed descriptions of the genotype and phenotype of FMF are given and the course of the pregnancy and fetal development are reported.\n\n\nRESULTS\nThe data of three patients and a total of four pregnancies under treatedment with anakinra were analyzed. All patients were of Mediterranean origin, fulfilled the Tel Hashomer criteria for diagnosis of FMF and had a confirmed mutation in the MEFV gene. In all patients, treatment with anakinra was initiated due to an insufficient treatment response to colchicine. Anakinra led to a rapid response in all patients. In three pregnancies anakinra treatment was continued during the whole pregnancy, while in one pregnancy anakinra was started in the second trimester because of uncontrolled FMF activity. Fetal development was normal in all pregnancies. In two patients the fetuses were carried to term, while in one patient a primary cesarean section was carried out in week 33 because of an increased risk for complications. All children showed an unremarkable early childhood development without any signs of an existing disease.\n\n\nCONCLUSIONS\nThe data of our retrospective analysis suggest that IL-1-blockade by anakinra is an effective and safe treatment in pregnant women suffering from FMF, which can reliably prevent disease flares. In the four pregnancies presented the use of anakinra did not result in impaired fetal and (early) childhood development.",
"affiliations": "Klinik für Rheumatologie und Klinische Immunologie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, 79106, Freiburg, Deutschland.;Klinik für Rheumatologie und Klinische Immunologie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, 79106, Freiburg, Deutschland.;Klinik für Rheumatologie und Klinische Immunologie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, 79106, Freiburg, Deutschland. cornelia.glaser@uniklinik-freiburg.de.;Klinik für Rheumatologie und Klinische Immunologie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, 79106, Freiburg, Deutschland.",
"authors": "Venhoff|N|N|;Voll|R E|RE|;Glaser|C|C|;Thiel|J|J|",
"chemical_list": "D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; C000604192:MEFV protein, human; D000071198:Pyrin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00393-017-0354-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-1855",
"issue": "77(2)",
"journal": "Zeitschrift fur Rheumatologie",
"keywords": "Anakinra; Familial Mediterranean fever (FMF); IL‑1‑blockade; Off-label; Pregnancy",
"medline_ta": "Z Rheumatol",
"mesh_terms": "D002585:Cesarean Section; D002648:Child; D010505:Familial Mediterranean Fever; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D000071198:Pyrin; D012189:Retrospective Studies",
"nlm_unique_id": "0414162",
"other_id": null,
"pages": "127-134",
"pmc": null,
"pmid": "28752409",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": "28293457;20191511;9336425;26337145;24924605;18771840;26888948;1285892;20579964;9500348;21063826;23981183;19302049;9668175",
"title": "IL-1-blockade with Anakinra during pregnancy : Retrospective analysis of efficacy and safety in female patients with familial Mediterranean fever.",
"title_normalized": "il 1 blockade with anakinra during pregnancy retrospective analysis of efficacy and safety in female patients with familial mediterranean fever"
} | [
{
"companynumb": "DE-BIOVITRUM-2017DE0761",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ANAKINRA"
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"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo determine the frequency of development of hepatocellular carcinoma in patients with chronic liver disease secondary to hepatitis C who had achieved sustained virological response with Interferon and Ribavirin therapy.\n\n\nMETHODS\nRetrospective descriptive study.\n\n\nMETHODS\nShifa International Hospital, Islamabad, Pakistan, from January 2007 to January 2012.\n\n\nMETHODS\nHepatitis C related chronic liver disease patients who were treated with interferon and ribavirin, after they achieved sustained virological response, they were followed for a mean of 42 ± 17 months. During this time, development of hepatocellular carcinoma was ascertained. All underwent surveillance with alpha-feto-protein and ultrasonography every 6 months.\n\n\nRESULTS\nOut of the 58 patients who had achieved sustained virological response, 3 developed hepatocellular carcinoma after a mean follow-up of 38 ± 14 months. It was multifocal in 2 cases and was single lesion in the 3rd. Two patients ultimately died, one with upper GI bleeding and the other with hepatic encephalopathy, while 3rd patient with single lesion is still surviving.\n\n\nCONCLUSIONS\nThree out of 58 patients of hepatitis C related chronic liver disease developed hepatocellular carcinoma during follow-up in patients who had achieved sustained virological response. These patients need closer follow-up, for development of complications, even if they have achieved sustained viral response.",
"affiliations": "Department of Gastroenterology / Medicine, Shifa International Hospital, Islamabad.",
"authors": "Khokhar|Nasir|N|;Niazi|Tariq Khan|TK|;Qureshi|Muhammad Omar|MO|",
"chemical_list": "D000998:Antiviral Agents; D012367:RNA, Viral; D012254:Ribavirin; D007372:Interferons",
"country": "Pakistan",
"delete": false,
"doi": "10.2013/JCPSP.699702",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-386X",
"issue": "23(10)",
"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D006528:Carcinoma, Hepatocellular; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006526:Hepatitis C; D006801:Humans; D015994:Incidence; D007372:Interferons; D008103:Liver Cirrhosis; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D010154:Pakistan; D012367:RNA, Viral; D012189:Retrospective Studies; D012254:Ribavirin; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9606447",
"other_id": null,
"pages": "699-702",
"pmc": null,
"pmid": "24112253",
"pubdate": "2013-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hepatocellular carcinoma after sustained viral response to interferon and ribavirin therapy in cirrhosis secondary to chronic hepatitis C.",
"title_normalized": "hepatocellular carcinoma after sustained viral response to interferon and ribavirin therapy in cirrhosis secondary to chronic hepatitis c"
} | [
{
"companynumb": "PK-KADMON PHARMACEUTICALS, LLC-KAD201311-001496",
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"activesubstancename": "RIBAVIRIN"
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"abstract": "Intestinal perforation is a rare adverse event of antineoplastic therapy. However, once it occurs, it is potentially fatal. This report describes a case of intestinal perforation caused by bevacizumab in a patient with ovarian cancer who concurrently developed neutropenic enterocolitis. A 66-year-old woman diagnosed with metastatic ovarian cancer received combination chemotherapy with carboplatin, gemcitabine, and bevacizumab. On day 14, she developed grade 4 pancytopenia and febrile neutropenia, which resulted in neutropenic enterocolitis and intestinal perforation. Emergency surgery was performed, and an intestinal perforation found in the ascending colon was closed. Postoperatively, she developed an intra-abdominal abscess requiring peritoneal drainage. She was discharged from the hospital on recovery.",
"affiliations": "Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.;Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.",
"authors": "Sasaki|Akinori|A|;Harano|Kenichi|K|https://orcid.org/0000-0002-0833-3489;Kogawa|Takahiro|T|;Matsubara|Nobuaki|N|;Naito|Yoichi|Y|;Hosono|Ako|A|;Mukai|Hirofumi|H|;Yoshino|Takayuki|T|;Mukohara|Toru|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/7231358",
"fulltext": "\n==== Front\nCase Rep Oncol Med\nCase Rep Oncol Med\nCRIONM\nCase Reports in Oncological Medicine\n2090-6706 2090-6714 Hindawi \n\n10.1155/2020/7231358\nCase Report\nIntestinal Perforation due to Neutropenic Enterocolitis in a Patient Treated with Bevacizumab for Ovarian Cancer\nSasaki Akinori \n1\n\n2\n https://orcid.org/0000-0002-0833-3489Harano Kenichi kharano@east.ncc.go.jp\n1\n Kogawa Takahiro \n1\n Matsubara Nobuaki \n1\n Naito Yoichi \n1\n Hosono Ako \n1\n Mukai Hirofumi \n1\n Yoshino Takayuki \n2\n Mukohara Toru \n1\n \n1Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan\n\n2Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan\nAcademic Editor: Mauro Cives\n\n\n2020 \n16 6 2020 \n2020 72313588 11 2019 28 5 2020 2 6 2020 Copyright © 2020 Akinori Sasaki et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Intestinal perforation is a rare adverse event of antineoplastic therapy. However, once it occurs, it is potentially fatal. This report describes a case of intestinal perforation caused by bevacizumab in a patient with ovarian cancer who concurrently developed neutropenic enterocolitis. A 66-year-old woman diagnosed with metastatic ovarian cancer received combination chemotherapy with carboplatin, gemcitabine, and bevacizumab. On day 14, she developed grade 4 pancytopenia and febrile neutropenia, which resulted in neutropenic enterocolitis and intestinal perforation. Emergency surgery was performed, and an intestinal perforation found in the ascending colon was closed. Postoperatively, she developed an intra-abdominal abscess requiring peritoneal drainage. She was discharged from the hospital on recovery.\n==== Body\n1. Introduction\nVascular endothelial growth factor (VEGF) A is a proangiogenic growth factor, which stimulates the proliferation, migration, and survival of endothelial cells. VEGF also plays a role in tumor growth and is the key target of certain antitumor drugs [1]. Bevacizumab, a humanized anti-VEGF monoclonal IgG1 antibody, inhibits neovascularization in tumor tissue and reduces the pressure of the tumor tissue framework [2]. The efficacy of bevacizumab has been proven in colorectal, breast, ovarian, and non-small-cell lung cancers [3–6]. Gastrointestinal perforation, known to be potentially fatal, is a rare adverse effect of bevacizumab therapy. Although neutropenic enterocolitis occurs in patients with neutropenia, it rarely leads to intestinal perforation [7]. Surgery for intestinal perforation carries high risk in patients with neutropenic enterocolitis owing to associated neutropenia and thrombocytopenia.\n\nThis report describes our experience with a patient who developed intestinal perforation due to the combined effect of neutropenic enterocolitis and bevacizumab.\n\n2. Case Presentation\nA 66-year-old Japanese woman presented with symptoms of abdominal distension and anorexia and was diagnosed with ovarian cancer (clear cell carcinoma), stage IIIC. She received neoadjuvant combination chemotherapy with carboplatin (AUC 5, day 1, every 3 weeks) and paclitaxel (175 mg/m2, day 1, every 3 weeks). She experienced grade 2 neutropenia during the first cycle; however, she recovered from this adverse event without the complication of infections. In addition, she achieved partial response in CT after two cycles of chemotherapy. Interval debulking surgery (IDS) was performed after seven cycles of this chemotherapy. Total hysterectomy, salpingo-oophorectomy, and infracolic omentectomy were performed for this patient. No major postoperative complications were observed in this case. On recovery, she received two cycles of adjuvant chemotherapy. Despite achieving complete response following treatment, she presented with recurrent peritoneal dissemination of the tumor, seven months after the last chemotherapy cycle. She was diagnosed with platinum-sensitive relapsed ovarian cancer and was prescribed combination chemotherapy with carboplatin (AUC 4, day 1, every 3 weeks), gemcitabine (1000 mg/m2, days 1 and 8, every 3 weeks), and bevacizumab (15 mg/kg, day 1, every 3 weeks).\n\nShe did not experience any adverse events for several days after administration of second-line chemotherapy. However, on day 14 of the first cycle, she presented to the hospital with fever and was subsequently diagnosed with febrile neutropenia owing to severe reductions in absolute neutrophil counts, which was evident from the laboratory data (Table 1). She also had thrombocytopenia of grade 4 and was suspected to have neutropenic enterocolitis owing to the presence of nausea and watery diarrhea, without any abdominal pain. After admission to the hospital, she received platelet transfusions and antibiotics, in addition to granulocyte colony-stimulating factor (G-CSF). On day 17, she complained of acute abdominal pain. The whole abdomen was tender on palpation, and rebound tenderness was elicited. Computed tomography was performed, which demonstrated thickening of the bowel wall with gastrointestinal perforation (Figure 1). She then underwent emergency surgery. Intraoperatively, the peritoneal cavity revealed turbid ascitic fluid exceeding 1000 mL in volume, with numerous white nodules characteristic of peritoneal dissemination. The entire intestine was markedly edematous, fragile, and inflamed, suggestive of neutropenic enterocolitis. The perforation site, which was markedly edematous, was detected in the ascending colon. A closure of the perforation was performed with placement of an intraperitoneal drain. The postoperative period was complicated with the development of an intra-abdominal abscess, requiring the placement of an additional drain, with appropriate antibiotics. Her condition improved gradually, and she was discharged from the hospital on day 56 after a complete recovery.\n\n3. Discussion\nIn the present case, intestinal perforation was induced by bevacizumab in the presence of neutropenic enterocolitis. Intestinal perforation is a fatal condition, particularly in neutropenic patients; urgent surgical intervention is essential for its management. Prompt assessment and formulation of a management plan are key factors in improving patient outcomes. In the present case, treatment of the intestinal perforation was successful owing to early detection and treatment.\n\nBevacizumab, a humanized anti-VEGF monoclonal IgG1 antibody, has demonstrated clinical benefit in ovarian cancer and has been available in Japan since 2013. Although bevacizumab shows considerable benefits, several adverse events have been reported with its use. Gastrointestinal adverse events are common with bevacizumab, and nausea, anorexia, and constipation are frequent. However, gastrointestinal perforation is a rare event, occurring in 0.9% to 3% of these patients [8–10]; it leads to severe peritonitis, which is a potentially fatal adverse event, with mortality rates exceeding 20% [11]. Bevacizumab-induced gastrointestinal perforations may be caused by various mechanisms. A previous study had speculated that bevacizumab possibly damages the structural and functional integrity of the gastrointestinal vasculature, causing ischemic perforation [12]. A report suggested that bevacizumab prevents healing of intestinal inflammation and ulcers, which leads to subsequent perforations [13].\n\nSeveral risk factors predispose patients to develop gastrointestinal perforation. Medical conditions associated with increased risk of perforation include prior bowel surgeries, bowel obstruction/ileus, diverticulitis, and rectovaginal nodularity [14]. Certain types of cancer, including ovarian cancer, also predispose to gastrointestinal perforation. It has been reported that gastrointestinal perforations occur in 15% of patients treated with bevacizumab for ovarian cancer [15]. Treatment-related factors for gastrointestinal perforation include abdominal irradiation, bowel surgery, nonsteroidal anti-inflammatory drugs (NSAIDs), and steroids.\n\nIn the present case, neutropenic enterocolitis was probably responsible for increasing the risk of intestinal perforation associated with bevacizumab. Neutropenic enterocolitis occurs as a result of injury to gut mucosal integrity in severely neutropenic patients. It follows treatment with cytotoxic chemotherapy, including carboplatin and paclitaxel [16]. It is however rare, occurring in about 5% of neutropenic patients [17]. Despite the low incidence, it is associated with very high mortality rates, exceeding 50%. Clinically, neutropenic enterocolitis is characterized by fever and abdominal pain, particularly in the right lower quadrant [18]. Additional bacterial invasion of the damaged bowel wall may lead to transmural inflammation and subsequent perforation. Peritoneal signs and shock clinically indicate the possibility of intestinal perforation. CT could be a useful tool in the diagnosis as it adequately demonstrates bowel wall thickening, bowel dilation, and pericolonic inflammation [19]. These findings were all noted in the present case.\n\nTwo factors, namely, the administration of bevacizumab and the occurrence of neutropenic enterocolitis, might have synergistically led to gastrointestinal perforation in the present case. The bowel wall might have been initially inflamed and damaged by bacterial invasion resulting from neutropenic enterocolitis; concurrent bowel ischemia induced by bevacizumab probably prevented healing of the intestinal mucosa, contributing to intestinal perforation. Since it is a rare complication, neutropenic enterocolitis has not been recognized as a risk factor for gastrointestinal perforation.\n\nThe present patient also had thrombocytopenia of grade 4 on admission. Although severe pancytopenia is rare in patients receiving the gemcitabine/carboplatin plus bevacizumab regimen, it is a severe adverse event [3]. Severe thrombocytopenia is potentially fatal, and surgery is contraindicated in many cases. In the present case, the patient was able to undergo surgery and had recovered gradually from the intestinal perforation despite concurrent pancytopenia of grade 4 and neutropenic enterocolitis.\n\nTo the best of our knowledge, this is the first reported case of intestinal perforation resulting from neutropenic enterocolitis in a patient treated with gemcitabine/carboplatin plus bevacizumab for ovarian cancer. Neutropenic enterocolitis is very rare among patients treated with bevacizumab. However, it is necessary to recognize the considerable increase in the risk of bevacizumab-related gastrointestinal perforation in patients having neutropenic enterocolitis consequent to cytotoxic chemotherapy.\n\nIn conclusion, bevacizumab in conjunction with neutropenic enterocolitis led to intestinal perforation in this patient with ovarian cancer. Patients undergoing treatment with bevacizumab should be carefully evaluated for concurrent neutropenia. In the event of intestinal perforation, it is essential to institute immediate and appropriate measures for management.\n\nConflicts of Interest\nThe authors declare no conflicts of interest.\n\nFigure 1 The abdominal CT findings. Abdominal CT showed free air (single arrow) and thickening of the bowel wall (arrowhead).\n\nTable 1 Laboratory data of posttreatment day 14. Decline of leukocytes, neutrophils, and platelets. Elevation of C-reactive protein. A blood gas analysis did not show any abnormal data.\n\nLaboratory data\t\nComplete blood count\t\n WBC\t400\t/μL\t\n Neutrophil\t130\t/μL\t\n RBC\t2.97\t×106/μL\t\n Hb\t8.7\tg/dL\t\n Hct\t25.4\t%\t\n Plt\t1.0\t×104/μL\t\nBlood coagulation test\t\n PT\t108\t%\t\n PT-INR\t0.97\t\t\n APTT\t28.3\tSeconds\t\nBlood gas analysis\t\n pH\t7.46\t\t\n PaO2\t83.0\tmmHg\t\n PaCO2\t39.3\tmmHg\t\n HCO3\t27.3\tmmol/L\t\n BE\t3.3\tmEq/L\t\n Lactate\t16\tmg/dL\t\nBlood biochemical test\t\n TP\t5.2\tg/dL\t\n Alb\t2.3\tg/dL\t\n T-bil\t0.7\tmg/dL\t\n AST\t25\tIU/L\t\n ALT\t23\tIU/L\t\n LDH\t233\tIU/L\t\n CK\t24\tIU/L\t\n BUN\t19\tmg/dL\t\n Creatine\t0.5\tmg/dL\t\n Na\t142\tmmol/L\t\n K\t3.2\tmmol/L\t\n Cl\t103\tmmol/L\t\n Ca\t8.2\tmg/dL\t\n CRP\t16.5\tmg/dL\n==== Refs\n1 Mancuso M. R. Davis R. Norberg S. M. Rapid vascular regrowth in tumors after reversal of VEGF inhibition The Journal of Clinical Investigation 2006 116 10 2610 2621 10.1172/JCI24612 2-s2.0-33749441325 17016557 \n2 Jain R. K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy Nature Medicine 2001 7 9 987 989 10.1038/nm0901-987 2-s2.0-0034796595 11533692 \n3 Burger R. A. Brady M. F. Bookman M. A. Incorporation of bevacizumab in the primary treatment of ovarian cancer The New England Journal of Medicine 2011 365 26 2473 2483 10.1056/NEJMoa1104390 2-s2.0-84855425106 22204724 \n4 Saltz L. B. Clarke S. Diaz-Rubio E. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study Journal of Clinical Oncology 2008 26 12 2013 2019 10.1200/JCO.2007.14.9930 2-s2.0-42949149159 18421054 \n5 Barlesi F. Scherpereel A. Rittmeyer A. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089) Journal of Clinical Oncology 2013 31 24 3004 3011 10.1200/JCO.2012.42.3749 2-s2.0-84886385462 23835708 \n6 Miller K. Wang M. Gralow J. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer The New England Journal of Medicine 2007 357 26 2666 2676 10.1056/NEJMoa072113 2-s2.0-37549040613 18160686 \n7 Rolston K. V. Bodey G. P. Safdar A. Polymicrobial infection in patients with cancer: an underappreciated and underreported entity Clinical Infectious Diseases 2007 45 2 228 233 10.1086/518873 2-s2.0-34447103022 17578784 \n8 Hurwitz H. Fehrenbacher L. Novotny W. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer The New England Journal of Medicine 2004 350 23 2335 2342 10.1056/NEJMoa032691 2-s2.0-2542561964 15175435 \n9 Hapani S. Chu D. Wu S. Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis The Lancet Oncology 2009 10 6 559 568 10.1016/S1470-2045(09)70112-3 2-s2.0-66149121478 19482548 \n10 Saif M. W. Elfiky A. Salem R. R. Gastrointestinal perforation due to bevacizumab in colorectal cancer Annals of Surgical Oncology 2007 14 6 1860 1869 10.1245/s10434-006-9337-9 2-s2.0-34249894171 17356952 \n11 Sliesoraitis S. Tawfik B. Bevacizumab-induced bowel perforation The Journal of the American Osteopathic Association 2011 111 7 437 441 21803880 \n12 Abbrederis K. Kremer M. Schuhmacher C. Ischemic anastomotic bowel perforation during treatment with bevacizumab 10 months after surgery Der Chirurg 2008 79 4 351 355 10.1007/s00104-007-1339-z 2-s2.0-42449136217 17453167 \n13 Tol J. Cats A. Mol L. Gastrointestinal ulceration as a possible side effect of bevacizumab which may herald perforation Investigational New Drugs 2008 26 4 393 397 10.1007/s10637-008-9125-4 2-s2.0-45849103519 18335169 \n14 Janos L. T. G. M. Andrea R. H. George C. Stephen C. R. John B. L. Christina S. C. Clinical predictors of bevacizumab-associated gastrointestinal perforation Gynecologic Oncology 2011 120 3 464 469 10.1016/j.ygyno.2010.11.009 2-s2.0-79951576333 21168199 \n15 Han E. S. Monk B. J. What is the risk of bowel perforation associated with bevacizumab therapy in ovarian cancer? Gynecologic Oncology 2007 105 1 3 6 10.1016/j.ygyno.2007.01.038 2-s2.0-33947311852 17383545 \n16 Davila M. L. Neutropenic enterocolitis Current Opinion in Gastroenterology 2006 22 1 44 47 10.1097/01.mog.0000198073.14169.3b 2-s2.0-33644828332 16319675 \n17 Gorschluter M. Mey U. Strehl J. Neutropenic enterocolitis in adults: systematic analysis of evidence quality European Journal of Haematology 2005 75 1 1 13 10.1111/j.1600-0609.2005.00442.x 2-s2.0-21044456878 15946304 \n18 Hsu T.-f. Huang H.-H. Yen D. H.-T. ED presentation of neutropenic enterocolitis in adult patients with acute leukemia The American Journal of Emergency Medicine 2004 22 4 276 279 10.1016/j.ajem.2004.02.014 2-s2.0-3142671586 15258868 \n19 Kirkpatrick I. D. Greenberg H. M. Gastrointestinal complications in the neutropenic patient: characterization and differentiation with abdominal CT Radiology 2003 226 3 668 674 10.1148/radiol.2263011932 2-s2.0-0037371586 12601214\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2020()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
"mesh_terms": null,
"nlm_unique_id": "101581035",
"other_id": null,
"pages": "7231358",
"pmc": null,
"pmid": "32612862",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "18335169;21803880;11533692;18160686;22204724;17578784;15258868;18421054;21168199;17383545;19482548;15175435;15946304;16319675;12601214;23835708;17356952;17016557;17453167",
"title": "Intestinal Perforation due to Neutropenic Enterocolitis in a Patient Treated with Bevacizumab for Ovarian Cancer.",
"title_normalized": "intestinal perforation due to neutropenic enterocolitis in a patient treated with bevacizumab for ovarian cancer"
} | [
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"companynumb": "JP-PFIZER INC-2020272372",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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"actiondrug": "5",
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"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
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{
"abstract": "Clinicians and researchers have long struggled to find effective treatments for people with anorexia nervosa (AN). Although most clinical guidance suggests that selective-serotonin reuptake inhibitor (SSRI) medication is not an effective first-line treatment for AN, in practice, these medicines continue to be frequently prescribed for comorbid diagnoses.\n\n\n\nIn this case report, two adolescents who were in sustained remission from AN either relapsed or began to decline significantly once their dose of SSRI medication was tapered.\n\n\n\nIn Case A, despite a very slow and measured taper, this child dropped significant weight in a short amount of time after the medication was discontinued. Fortunately for Case B, symptoms emerged before the taper was complete, and providers could quickly increase the dose of medication early in her struggle with AN thoughts and urges.\n\n\n\nA brief review of literature regarding SSRI medication use in AN is presented along with considerations for future research.",
"affiliations": "West Virginia University Department of Behavioral Medicine and Psychiatry, WVU School of Medicine - Charleston Division, Charleston, West Virginia.;Psychiatry Residency, Charleston Area Medical Center, Charleston, West Virginia.;West Virginia University Department of Behavioral Medicine and Psychiatry, WVU School of Medicine - Charleston Division, Charleston, West Virginia.",
"authors": "Luzier|Jessica|J|0000-0003-2617-4968;Rached|Kristina|K|;Talley|Jessica|J|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1002/eat.23092",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0276-3478",
"issue": "52(7)",
"journal": "The International journal of eating disorders",
"keywords": "adolescent; anorexia nervosa; eating disorder; medication; relapse",
"medline_ta": "Int J Eat Disord",
"mesh_terms": "D000293:Adolescent; D000856:Anorexia Nervosa; D002648:Child; D005260:Female; D006801:Humans; D055502:Secondary Prevention; D017367:Serotonin Uptake Inhibitors; D016896:Treatment Outcome",
"nlm_unique_id": "8111226",
"other_id": null,
"pages": "863-867",
"pmc": null,
"pmid": "31081553",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Relapse prevention and selective serotonin reuptake inhibitor medication in two adolescents with anorexia nervosa.",
"title_normalized": "relapse prevention and selective serotonin reuptake inhibitor medication in two adolescents with anorexia nervosa"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0113025",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
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... |
{
"abstract": "Oseltamivir is the most common antiviral drug used to treat and prevent influenza. Epidemiological studies performed in Japan, the United States, and the United Kingdom indicate that oseltamivir may cause psychiatric symptoms; however, the underlying mechanism has not been elucidated. In South Korea, interest in oseltamivir has increased with the spread of the new influenza virus; however, no case report or investigation of psychiatric symptoms associated with the drug has been reported to date. Here, we report a case of a 22-year-old male who complained of mood swings, suicidal feelings, auditory hallucinations, memory deterioration, and insomnia after taking oseltamivir.",
"affiliations": "Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea.;Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea.",
"authors": "Jeon|Sang Won|SW|;Han|Changsu|C|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.9758/cpn.2015.13.2.209",
"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 2624385010.9758/cpn.2015.13.2.209cpn-13-209Case ReportPsychiatric Symptoms in a Patient with Influenza A (H1N1) Treated with Oseltamivir (Tamiflu): A Case Report Jeon Sang Won Han Changsu Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, \nKoreaAddress for correspondence: Changsu Han, MD, PhD, Department of Psychiatry, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan 15355, Korea, Tel: +82-31-412-4931, Fax: +82-31-412-5144, E-mail: hancs@korea.ac.kr8 2015 31 8 2015 13 2 209 211 09 12 2014 30 12 2014 31 12 2014 Copyright © 2015, Korean College of Neuropsychopharmacology2015This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Oseltamivir is the most common antiviral drug used to treat and prevent influenza. Epidemiological studies performed in Japan, the United States, and the United Kingdom indicate that oseltamivir may cause psychiatric symptoms; however, the underlying mechanism has not been elucidated. In South Korea, interest in oseltamivir has increased with the spread of the new influenza virus; however, no case report or investigation of psychiatric symptoms associated with the drug has been reported to date. Here, we report a case o0f a 22-year-old male who complained of mood swings, suicidal feelings, auditory hallucinations, memory deterioration, and insomnia after taking oseltamivir.\n\nOseltamivirTamifluHuman influenzaPsychiatric symptomSide effect\n==== Body\nINTRODUCTION\nOseltamivir (Tamiflu; F. Hoffmann-La Roche, Ltd., Basel, Switzerland) is the most frequently used antiviral agent for the treatment and prevention of influenza, and its use has increased since the influenza A (H1N1) epidemic.1,2) With the increased use of oseltamivir, psychiatric symptoms have been reported as side effects. Between 1999 and 2007, a total of 480 million patients worldwide were administered oseltamivir, and psychiatric side effect surveys were conducted in Japan (n=2,772), the United States (n=190), and other countries (n=89).3) Psychiatric side effects were more common in infants and children aged 16 years or younger than in adults (2,218 children vs. 833 adults),4) and generally occurred within 48 hours of receiving oseltamivir.5,6) According to the International Classification of Diseases 10th revision (ICD-10), the major symptoms include abnormal behavior (1,160 events, 38%), delusions/perceptual disturbances (661 events, 21.7%), and delirium or delirium-like events.3–7) These side effects may lead to accidents, injuries, or suicides.\n\nUnlike research abroad, few studies of the psychiatric side effects of oseltamivir have been conducted in South Korea. Moreover, despite various epidemiological and experimental studies, few studies have investigated the entire disease cycle from symptom onset and treatment through follow up. It is likely that the extensive use of oseltamivir to treat influenza will continue into the future; thus, it is important that attention be given to the psychiatric side effects of the drug.\n\nCASE\nA 22-year-old male visited our psychiatry clinic with the major complaints of mood swings, suicidal impulses, auditory hallucinations, memory deterioration, and insomnia, which had occurred several times a day for the past 5 days. He had no personal or familial psychiatric history. He was well adjusted and had no problems with his family or other relationships. Twelve days earlier, the patient had developed fever and respiratory symptoms suspected to be indicative of influenza A (H1N1). Ten days before his visit, he was prescribed 75 mg oseltamivir (Tamiflu) and 650 mg acetaminophen (Tylenol ER; Janssen Korea, Ltd., Seoul, Korea), which he took in the morning and evening daily for 5 days. Nine days before his visit, the diagnosis was confirmed by an influenza A (H1N1) polymerase chain reaction (PCR) test, and he continued to take Tamiflu as scheduled. During the 5 days that he was taking Tamiflu, the patient continued his normal routine, but felt a slight deterioration in mood and memory and suffered from insomnia. The patient’s fever and respiratory symptoms were in remission 3 days after the initiation of Tamiflu; however, the deterioration in his mood and memory and the insomnia did not improve significantly. The next day, when he finished the 5-day course of Tamiflu, he started to develop significant psychiatric symptoms. He experienced manic symptoms for periods ranging from 10 minutes to 2 hours and then abruptly felt depressed and burst into tears with frequent nihilistic and sin delusions. Two days after he finished taking Tamiflu and 3 days before his visit, the patient’s mood swings and instability grew worse, and he experienced auditory hallucinations similar to a telephone conversation between a man and a woman and text message alarm ringtones for mobile phones. Because of his memory deterioration, the patient readily forgot what he had done several hours or days earlier. He was not able to sleep more than 2–3 hours a day. Eventually, the patient visited our psychiatric clinic and was admitted under the suspicion of bipolar disorder, an organic mental disorder such as delirium and encephalitis, and psychotic disorders caused by his drug intake.\n\nThe patient was admitted to the closed ward and treated with antipsychotic medication by 10 mg intramuscular olanzapine (Zyprexa; Eli Lilly and Company, Ltd., Indianapolis, IN, USA) and 10 mg oral olanzapine. After drug treatment, the patient was able to sleep for 9 hours. The next morning, his suicidal ideas had disappeared, his mood swings decreased, and the frequency and intensity of his auditory hallucination were reduced significantly.\n\nSingle-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) scans performed the second day after the patient was admitted to hospital yielded normal findings with no deterioration in brain function or activity and no changes in brain structure. The electroencephalogram (EEG) showed no abnormal brain-wave patterns, and the neurological examinations revealed no abnormal findings. Physical examinations (blood test, serum electrolyte, blood glucose, blood urea nitrogen, creatinine, liver function test, serum syphilis, HIV test, thyroid function test, serum vitamin B12, folate), chest X-ray, electrocardiogram, and urine tests all showed normal results. The patient did not have a history of drug use, and the result of his urine drug-screening test was negative. The influenza A (H1N1) PCR test was repeated, and a negative result was confirmed. The patient received 5 mg olanzapine orally on day 2 following admission to the hospital, after which he showed a normal sleep pattern.\n\nFrom day 3 after admission, the patient’s mood and behaviors became normal, and no auditory hallucinations or memory deterioration were observed. Given the rapid improvement in his symptoms, antipsychotic medication was ceased. Psychiatric observation, which was continued until day 8, revealed no specific psychiatric symptoms. He talked about his symptoms with an ego-dystonic attitude and a high insight level. On day 8 after admission, the patient was discharged based on his normal test findings and psychiatric observation results. No drug prescription was made. The discharge diagnosis was ‘mental and behavioral disorder due to the use of other psychoactive substances’ (F19.8; ICD-10).\n\nHe was followed up 2 weeks after discharge, at which point, he had adjusted to his normal daily routine. The absence of symptoms was confirmed at the next follow-up 4 weeks after discharge. At 10 months after discharge, the patient successfully managed his daily life with no psychiatric symptoms.\n\nDISCUSSION\nWe describe a patient with psychiatric symptoms that resulted from oseltamivir intake following an influenza A (H1N1) infection. Several factors pointed toward oseltamivir as the cause of the patient’s psychiatric symptoms. First, involvement of other psychiatric conditions was ruled out by psychiatric interviews and assessments, and the presence of organic mental conditions and psychotic disorders caused by the intake of other medications was excluded through physical examinations, brain imaging scans, and EEG. Second, the patient’s symptoms were similar to those reported in previous studies of psychiatric symptoms associated with oseltamivir. Third, the patient was highly responsive to antipsychotic medications and fully recovered in a short period of time, which suggested drug-induced psychosis. Fourth, because the patient was unaware of the side effects of oseltamivir and the possibility of developing psychiatric symptoms, he did not have a bias or a sensitive response to the drug. Fifth, the patient’s symptoms were confirmed to have developed independently during the time of the medication intake, and he showed no symptoms during a 10-month follows-up period after the reversal of his symptoms.\n\nHowever, our patient showed some differences from previously described cases. It has been known that psychiatric symptoms usually develop within 48 hours of oseltamivir intake5,6); however, in our case, the psychiatric symptoms became obvious 5 days after oseltamivir intake.\n\nThe mechanism underlying oseltamivir-induced psychiatric symptoms is not well understood. One hypothesis is that a neuraminidase inhibitor that has antiviral effects crosses the blood-brain barrier (BBB) into the central nervous system.8) Studies in mice have shown that although oseltamivir carboxylate, an oseltamivir metabolite, does not pass through the BBB readily, it may do so when combined with other agents or when the BBB is damaged.9) Moreover, oseltamivir carboxylate has been shown to cause neuronal excitability.10) A previous study found that plasma and brain oseltamivir carboxylate concentrations were higher in young mice than in adults, suggesting that oseltamivir is more likely to have adverse effects in infants and adolescents than in adults.11)\n\nBecause the effect of the influenza virus on the central nervous system is not fully understood, we are not able to conclude whether the symptoms experienced by our patient were consistent with the clinical course of influenza. Moreover, the symptoms may have been the result of immunological rather than influenza viral effects on the central nervous system.8,9) Complications of influenza, such as encephalitis and encephalopathy, can be diagnosed by neurological examinations and brain imaging. However, these techniques are not sufficient for the diagnosis of central nervous system complications not caused by the direct invasion of the influenza virus, such as immunological or unknown mechanisms.12)\n\nOseltamivir is generally prescribed in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) or antihistamine agents. The effect of interactions between oseltamivir and these agents on the central nervous system is poorly understood. The oseltamivir metabolite changes as it interacts with other drugs and may affect the central nervous system.9,10)\n\nPsychiatric side effects of oseltamivir have been reported more frequently in Japan than in the United States and Europe.3) This may be explained by the extensive use of oseltamivir during the influenza pandemic in Japan; however, genetic features associated with ethnicity or geographic factors may also contribute to the higher incidence of psychiatric symptoms.\n\nAlthough several studies have demonstrated that oseltamivir induces psychiatric symptoms, this issue remains under debate. Further study of the mechanisms underlying the psychiatric side effects of the drug is needed. In the meantime, close observation and follow-up are recommended when oseltamivir is administered for the treatment of influenza.\n==== Refs\nREFERENCES\n1 National Institute for Clinical Excellence Guidance on the use of zanamivir, olsetamivir and amantadine for the treatment of influenza: Technology appraisal guidance 4th ed Washington, DC National Institute for Clinical Excellence 2010 \n2 Turner D Wailoo A Nicholson K Cooper N Sutton A Abrams K Systematic review and economic decision modeling for the prevention and treatment of influenza A and B Health Technol Assess 2003 7 iii iv xi xiii 1 170 10.3310/hta7350 14609480 \n3 Toovey S Rayner C Prinssen E Chu T Donner B Thakrar B Assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review Drug Saf 2008 31 1097 1114 10.2165/0002018-200831120-00006 19026027 \n4 Maxwell SR Tamiflu and neuropsychiatric disturbance in adolescents BMJ 2007 334 1232 1233 10.1136/bmj.39240.497025.80 17569896 \n5 Fuyuno I Tamiflu side effects come under scrutiny Nature 2007 446 358 359 10.1038/446358a 17377552 \n6 US Food and Drug Administration Safety alerts for drugs, biologist, medical devices, and dietary supplements The FDA safety information and adverse event reporting program 12th ed New York US Food and Drug Administration 2011 \n7 US Ministry of Health Working group for clinical investigation for oseltamivir phosphate 1st ed Boston US Ministry of Health 2007 \n8 Matheson NJ Harnden AR Perera R Sheikh A Symmonds-Abrahams M Neuraminidase inhibitors for preventing and treating influenza in children Cochrane Database Syst Rev 2007 1 CD002744 17253479 \n9 Izumi Y Tokuda K O’Dell K Zorumski C Narahashi T Neuroexcitatory actions of Tamiflu and its carboxylate metabolite Neurosci Let 2007 426 54 58 10.1016/j.neulet.2007.08.054 17884292 \n10 Satoh K Nonaka R Ogata A Nakae D Uhehara S Effects of oseltamivir phosphate (Tamiflu) and its metabolite (GS4071) on monoamine neurotransmission in the rat brain Biol Pharm Bull 2007 30 1816 1818 10.1248/bpb.30.1816 17827748 \n11 Ose A Kusuhara H Yamatsugu K Kanai M Shibasaki M Fujita T P-glycoprotein restricts the penetration of oseltamivir across the blood-brain barrier Drug Metab Dispos 2008 36 427 434 10.1124/dmd.107.018556 18039806 \n12 Hama R Fatal neuropsychiatric adverse reactions to oseltamivir: Case series and overview of casual relationships Int J Risk Saf Med 2008 20 5 36\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1088",
"issue": "13(2)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Human influenza; Oseltamivir; Psychiatric symptom; Side effect; Tamiflu",
"medline_ta": "Clin Psychopharmacol Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101207332",
"other_id": null,
"pages": "209-11",
"pmc": null,
"pmid": "26243850",
"pubdate": "2015-08-31",
"publication_types": "D016428:Journal Article",
"references": "18039806;14609480;17377552;17569896;19026027;17253479;17827748;17884292",
"title": "Psychiatric Symptoms in a Patient with Influenza A (H1N1) Treated with Oseltamivir (Tamiflu): A Case Report.",
"title_normalized": "psychiatric symptoms in a patient with influenza a h1n1 treated with oseltamivir tamiflu a case report"
} | [
{
"companynumb": "KR-ROCHE-1619682",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OSELTAMIVIR PHOSPHATE"
},
"drugadditional": null,
... |
{
"abstract": "Temozolomide and capecitabine (CAPTEM) chemotherapy is known to be active in patients with pancreatic neuroendocrine tumours.\n\n\n\nThis retrospective analysis set out to describe the efficacy and toxicity of CAPTEM in patients with advanced pulmonary carcinoids (PCs).\n\n\n\nPatients were included with advanced PC who had been treated with a maximum of 6 cycles of oral temozolomide 200 mg/m2 on days 10-14 and capecitabine 750 mg/m2 b.i.d. on days 1-14, repeated every 28 days, -followed by monthly intramuscular injection of octreotide 30 mg long-acting release as maintenance treatment.\n\n\n\nOf the 33 patients, all with well-differentiated PC, 61% had atypical carcinoid, 36% had Ki-67 index >10% and 42% had ≥3 organs involved by metastasis. CAPTEM was administered as first-line treatment in 42% of patients, and 17% had received prior somatostatin analogue treatment. Six patients (18%) achieved a partial response, 19 (58%) had stable disease and 8 (24%) developed progressive disease. After a median time of follow-up of 34.8 months, median progression-free survival (PFS) was 9.0 months and median overall survival 30.4 months. Median duration of disease response was 21.7 months and median duration of disease control 9.7 months. Patients with multi-organ metastasis had shorter PFS, but only when treated as second or third line with CAPTEM (p = 0.023).\n\n\n\nCAPTEM induced a modest response and PFS rate, comparable to other studies with temozolomide in patients with advanced PC. The efficacy of CAPTEM should be compared to that of monotherapy with temozolomide in a prospective clinical trial.",
"affiliations": "Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.;Cellular Pathology, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom, was.mansoor@christie.nhs.uk.",
"authors": "Papaxoinis|George|G|;Kordatou|Zoe|Z|;McCallum|Lynne|L|;Nasralla|Magdy|M|;Lamarca|Angela|A|;Backen|Alison|A|;Nonaka|Daisuke|D|;Mansoor|Wasat|W|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D019394:Ki-67 Antigen; C000628856:MKI67 protein, human; D000069287:Capecitabine; D000077204:Temozolomide",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000502864",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3835",
"issue": "110(5)",
"journal": "Neuroendocrinology",
"keywords": "Capecitabine; Chemotherapy; Prognosis; Pulmonary carcinoids; Temozolomide; Well-differentiated neuroendocrine tumours",
"medline_ta": "Neuroendocrinology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D002276:Carcinoid Tumor; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors; D017063:Outcome Assessment, Health Care; D011379:Prognosis; D012189:Retrospective Studies; D000077204:Temozolomide",
"nlm_unique_id": "0035665",
"other_id": null,
"pages": "413-421",
"pmc": null,
"pmid": "31437838",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Capecitabine and Temozolomide in Patients with Advanced Pulmonary Carcinoid Tumours.",
"title_normalized": "capecitabine and temozolomide in patients with advanced pulmonary carcinoid tumours"
} | [
{
"companynumb": "GB-ROCHE-2418456",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nOur aim was to determine feasibility and effect sizes of bright light therapy (BLT), melatonin (MLT), methylphenidate (MP) and eight combinations (BLT+MLT+MP, BLT+MLT, BLT+MP, BLT alone, MLT+MP, MLT alone, MP alone, placebo for BLT, MLT and MP) defined as multimodal therapy (MMT), to improve sleep quality (SQ) (Pittsburgh Sleep Quality Index (PSQI)) from baseline to day 15. We also examined the effects of MMT on insomnia, fatigue, depression, quality of life and actigraphy.\n\n\nMETHODS\nPatients with advanced cancer with poor SQ (PSQI ≥5) were eligible. Using a double-blind randomised factorial study design, patients were randomised into 1 of the 8 arms for 2 weeks. Feasibility and effect sizes were assessed.\n\n\nRESULTS\n81% (54/67) of randomised patients completed the study. There were no differences in the demographics and SQ between groups. The adherence rates for BLT, MLT and MP were 93%, 100% and 100%, respectively. BLT+MLT+placebo of MP; BLT+placebo of MLT+placebo of MP; BLT+MLT+MP showed an effect size (Cohen's d) for change in PSQI scores of 0.64, 0.57 and 0.63, respectively. PSQI change using linear regression showed BLT (n=29) has effect size of 0.46, p=0.017; MLT (n=26), 0.24, p=0.20; MP (n=26), 0.06, p=0.46. No significant differences were observed in scores for insomnia, fatigue, depression, quality of life and actigraphy. There were no differences in adverse events by groups(p=0.80).\n\n\nCONCLUSIONS\nThe use of MMT to treat SQ disturbance was feasible. BLT+MLT showed the most promising effect size in improvement in SQ, and additional larger studies are needed.\n\n\nBACKGROUND\nNCT01628029.",
"affiliations": "Department of Palliative, Rehabilitation, and Integrative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA syennu@mdanderson.org.;Department of Palliative, Rehabilitation, and Integrative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Gastrointestinal Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.;Department of Breast Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Palliative, Rehabilitation, and Integrative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Palliative, Rehabilitation, and Integrative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Palliative, Rehabilitation, and Integrative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Palliative, Rehabilitation, and Integrative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Palliative, Rehabilitation, and Integrative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Palliative, Rehabilitation, and Integrative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Palliative, Rehabilitation, and Integrative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.",
"authors": "Yennurajalingam|Sriram|S|http://orcid.org/0000-0002-2910-8141;Carmack|Cindy|C|;Balachandran|Dave|D|;Eng|Cathy|C|;Lim|Bora|B|;Delgado|Marvin|M|;Guzman Gutierrez|Diana|D|;Raznahan|Monica|M|;Park|Minjeong|M|;Hess|Kenneth R|KR|;Williams|Janet L|JL|;Lu|Zhanni|Z|;Ochoa|Jewel|J|;Bruera|Eduardo|E|http://orcid.org/0000-0002-8745-0412",
"chemical_list": "D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D008550:Melatonin",
"country": "England",
"delete": false,
"doi": "10.1136/bmjspcare-2019-001877",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2045-435X",
"issue": "11(2)",
"journal": "BMJ supportive & palliative care",
"keywords": "cancer; light therapy; melatonin; methylphenidate; multimodal therapy; psychoeducation sessions",
"medline_ta": "BMJ Support Palliat Care",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000697:Central Nervous System Stimulants; D003131:Combined Modality Therapy; D004311:Double-Blind Method; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D008550:Melatonin; D008774:Methylphenidate; D008875:Middle Aged; D009369:Neoplasms; D010789:Phototherapy; D012890:Sleep; D007319:Sleep Initiation and Maintenance Disorders",
"nlm_unique_id": "101565123",
"other_id": null,
"pages": "170-179",
"pmc": null,
"pmid": "31924662",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Sleep disturbance in patients with cancer: a feasibility study of multimodal therapy.",
"title_normalized": "sleep disturbance in patients with cancer a feasibility study of multimodal therapy"
} | [
{
"companynumb": "US-SPECGX-T202000412",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nVirus encephalitis is found to be a risk factor for acute retinal necrosis (ARN).\n\n\nMETHODS\nWe herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later.\n\n\nCONCLUSIONS\nThe case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.",
"affiliations": "Department of Ophthalmology, Guangdong Eye Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.;Department of Ophthalmology, Guangdong Eye Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.;Department of Ophthalmology, Guangdong Eye Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.;Department of Ophthalmology, Guangdong Eye Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China. syyangxh@scut.edu.cn.",
"authors": "Zhong|Pingting|P|;Zang|Siwen|S|;Yu|Honghua|H|;Yang|Xiaohong|X|http://orcid.org/0000-0001-9466-7591",
"chemical_list": "D000998:Antiviral Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s12883-021-02082-2",
"fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377 BioMed Central London \n\n2082\n10.1186/s12883-021-02082-2\nCase Report\nHerpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report\nZhong Pingting 12 Zang Siwen 1 Yu Honghua 1 http://orcid.org/0000-0001-9466-7591Yang Xiaohong syyangxh@scut.edu.cn 1 1 Department of Ophthalmology, Guangdong Eye Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080 China \n2 grid.411679.c0000 0004 0605 3373Shantou University Medical College, Shantou, China \n2 2 2021 \n2 2 2021 \n2021 \n21 4912 9 2020 27 1 2021 © The Author(s) 2021Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nVirus encephalitis is found to be a risk factor for acute retinal necrosis (ARN).\n\nCase presentation\nWe herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later.\n\nConclusions\nThe case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.\n\nKeywords\nAcute retinal necrosisEncephalitisHerpes simplex virusSteroidsAntiviral treatmentScience and Technology Program of Guangzhou, China202002020049Yang Xiaohong Project of Investigation on Health Status of Employees in Financial Industry in Guangzhou Z012014075Yang Xiaohong issue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nAcute retinal necrosis (ARN) is a serious and potential blinding viral ocular infection, and it rapidly develops and progresses in immunocompetent people, causing uveitis with necrotizing retinitis [1]. Varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2 are the most common causative viruses of ARN [1]. It is assumed that reactivation amid immune dysfunction of the virus leads to ARN, along with central nervous system infection [2]. The association between viral encephalitis and ARN has been reported in one per 1.6–2.0 million people [3]. Therefore, additional attention with regard to ocular clinical manifestations is specially needed in patients with encephalitis after systemic treatment with steroids, as they could affect the body immunity and cause reactivation of the virus. Viral encephalitis should be aware of as it is a risk factor of ARN, and so antiviral treatment is recommended for suspected viral encephalitis.\n\nCase presentation\nA 20-year-old teenage boy with abrupt fever, confusion, and epileptic seizures was referred to the Department of Neurology of the Guangzhou General Military Hospital. The patient was otherwise a healthy boy until he had an unusual health status prior to 5 days. Cerebral spinal fluid (CSF) analysis was performed on admission, and the result showed negative Pandy test with a predominance of lymphocytes. Besides, CSF test for Mycobacterium tuberculosis, herpes simplex virus (HSV), cytomegalovirus (CMV), and rubella virus revealed negative results. Two days later, antibody analysis of autoimmune encephalitis was also shown to be normal. Brain magnetic resonance imaging (MRI) showed hypersignal intensity in bilateral frontal as well as temporal lobe.\n\nNext, the patient was diagnosed with encephalitis due to unidentified etiology, and then systemic administration of steroids was given without antiviral treatment. He was prescribed with intravenous methylprednisolone, 1 g/d for 3 consecutive days, followed by 0.5 g/d for 3 days, and then was maintained on 80 mg/d for 2 weeks. Two weeks after admission, the boy showed no sign of improvement. A second brain MRI showed much worsened manifestation of hypersignal in both bilateral frontal and temporal lobe, and a second CSF analysis showed negative results of the pathogen as shown in the first CSF analysis. He was therefore presumed to have “autoimmune encephalitis” by primary neurologists and was prescribed with gamma globulin 25 g/d for 5 days. Later, he had less fever and seizures, and improvements were observed in his oral expression. So, intravenous methylprednisolone administration was gradually reduced and replaced it by oral prednisone of 60 mg/d and then was discharged. One day after being discharged, he had sudden vision loss in his right eye, and then the boy was urgently referred to our hospital.\n\nInvestigations\nAfter admitting in our hospital, the patient’s physical and neurological exams were found to be unremarkable. His best corrected visual acuity (BCVA) showed light perception with correct light location in the temporal region of the right eye (OD), and 20/20 with that of the left eye (OS). Ophthalmological examination of his right eye revealed positive Tyndall (+) and cell (++) in the anterior chamber, with obvious opacity (+++) in the vitreous chamber. The fundus of his right eye showed yellow-white lesions, with narrowing retinal vessels and white-sheath and peripheral hemorrhage. Also several tiny retinal holes that lead to retinal detachment (RD) were observed in the peripheral retina (Fig. 1a). No remarkable changes were observed in his left eye.\nFig. 1 Fundus photographs of the right eye. a On admission. The blue arrows represent severe occlusive vasculitis, with macula involved in the peripheral retina, and white arrow represents several tiny holes on superior-nasal degeneration area. b On discharge day. Retinal detachment was repaired with retinal vasculitis and edema showed great improvement\n\n\n\nNew brain MRI performed in our hospital suggested multiple abnormal signals in the brain parenchyma, which were in accordance with the manifestations of viral encephalitis (Fig. 2). So, viral-related retinal disorders were highly suspected in our case. Vitreous humor was obtained through vitreous chamber tapping to perform polymerase chain reaction (PCR) analysis. DNA of HSV-1 virus (9.0 × 106/ml) was identified 5 days after intravitreal antiviral treatment, and the positive results of IgG and IgM antibodies in the blood serology also supported HSV-1 infection, thus confirming the diagnosis of ARN by HSV-1.\nFig. 2 Hypersignal intensity of left temporal lobe in MRI with T2 flair\n\n\n\nTreatment\nIntravitreal administration of ganciclovir (0.4 mg/ 0.1 ml) was immediately performed following vitreous chamber tapping at the time of admission to our hospital. Two days later, the boy was relieved from vitreous opacities (+). Antiviral treatment was therefore considered to be effective, and broad-spectrum antiviral medicine (ganciclovir 250 mg every 12-h) was started intravenously, and then replaced with intravenous acyclovir (500 mg every 8-h) after confirmation of HSV pathogen. As the patient also suffered from RD, his right eye was treated by pars plana vitrectomy (PPV), endolaser and silicone oil tamponade 3 days after admission. During the surgery, a second time intravitreal ganciclovir (0.4 mg/0.1 mg) was given.\n\nOutcomes and follow-up\nThe patient received intravenous antiviral treatment for 2 weeks and was discharged with oral antiviral medicine (famciclovir 375 mg twice a day) as planned for 3 to 4 months. On the day of discharge, BCVA was 20/80 OD and retinal edema in his right eye has been greatly relieved (Fig. 1b). At 5 weeks of follow-up, recurrent vision declination occurred with 20/500 OD due to recurrent RD (Fig. 3). Therefore, silicon oil displacement and endolaser were performed to repair the retina, as well as intravitreal ganciclovir (0.4 mg/0.1 mg) was given for third time. The BCVA of his right eye was increased to 20/80 within 3 days after the surgery. Six months later, after removing the silicone oil, the BCVA was shown to be 20/200 OD with complicated cataract.\nFig. 3 OCT images of the right eye. a On discharge day and b at 5 weeks after discharge\n\n\n\nDiscussion and conclusion\nOur patient due to encephalitis suffered from HSV related ARN after systemic administration of steroids. HSV-infected ARN could be a serious threat that leads to vision loss. Therefore, early awareness and timely antiviral treatment of suspected viral encephalitis are critical in such patients.\n\nThe possible reason for the cause of ARN in this patient might be due to viral encephalitis. HSV-1 virus encephalitis is usually characterized by altered mental health status, seizures, somnolence, increased cellularity with predominant lymphocytes in CSF, as well as hypersignal intensity in the MRI of temporal lobes [4], and all these clinical manifestations were observed in our patient. In our case, encephalitis was highly suspected to be caused by viral infection. However, lack of direct evidence of the virus in CSF impeded antiviral treatment. The patient later suffered from ARN due to HSV, suggesting that the virus might come from the brain. Due to the negative evidence in CSF, it could result in low positive predictive value [5] or procedural-related problems. To repeat CSF analysis is important in suspected viral encephalitis. ARN has been reported in cases with prior [6], simultaneous [7], or post [8] presence of herpetic simplex encephalitis or meningitis, and the interval between ARN and meningitis/encephalitis varied from 2 to 5 weeks [9]. A possible underlying mechanism has demonstrated bidirectional fast-axonal transport in neurons [10], and the viral genes play a critical role for antegrade and retrograde axonal transportation.\n\nImmunocompromise after systemic administration of high-dose steroids could be another possible reason for the triggering of ARN in the current case. There are several possible explanations for steroids contributing to the occurrence of ARN. Firstly, high-dose steroids might affect body immunity, promote viral replication, and worsen necrotizing retinopathy [11]. The virus might reach the eye from the brain by a trans-axonal route. Secondly, the triggering event of systemic administration of high-dose steroids could reactivate HSV infection [12], and the latent HSV in several sites is connected to the eye, finally resulting in herpetic ocular disease that involves the cornea, iris, or even the retina [13]. When treating patients with encephalitis, for whom systemic administration of steroids is an inevitable regimen, neurologists should be aware that it might lead to immunocompromise, posing a serious threat in triggering ARN. In addition, according to prior studies on treatment of HSV1-encephalitis by combining with acyclovir, a study showed that treatment without corticosteroid was associated with poorer outcomes [14], while another study found no positive effects by adding dexamethasone to acyclovir [15]. Therefore, the use of corticosteroid therapy for viral encephalitis depends on the discretion of clinicians. As patients with encephalitis always present with confusion, which prevents them from timely and precise expression of their ocular discomforts, and so attention should be paid with regard to ocular clinical manifestations.\n\nIntravitreal and intravenous antiviral treatment was then immediately started in this patient, and this is because of high suspicion of ARN according to ocular manifestations. So, diagnostic testing of vitreous humor before antiviral treatment has been done, and later corresponding adjustments were made. Topical and systemic antiviral treatment is an urgent need, as it is beneficial for the visual acuity and thus could decrease the risk of infection to the other eye [16]. As documented previously, there were up to 70% of untreated patients with bilateral ARN [17]. In our case, ARN was presented in a single eye, but it is assumed that the contralateral eye might also be affected if timely and precise antiviral treatment is not given. With a better understanding of antiviral treatment, the rate of bilateralization according to the recently reported studies on ARN has been found to be significantly decreased into 10–20% [18].\n\nThe challenges concerning diagnosis as well as prognosis were posed in this case. The CSF initially revealed negative results for viral encephalitis, and the diagnosis of ARN was later confirmed by PCR analysis with HSV-1 in the vitreous humor, and this is widely available to clinicians with good sensitivity and specificity [19]. According to a recent study, the correlation of quantitative DNA PCR and clinical prognosis in ARN has revealed that a number of copies superior to 5.0 × 106/ml showed association with a higher probability of RD [20]. In our case, the quantitative DNA of HSV-1 was 9.0 × 106/ml, suggesting a poor prognosis of vision in accordance with recurrent RD and vision declination during the follow-up period.\n\nIn the suspected case of viral encephalitis, antiviral therapy should be performed regardless of early PCR results to avoid complications of missed viral encephalitis, especially if systemic glucocorticoid therapy is being considered. Besides, special awareness and careful evaluation on neuro-ophthalmological assessment should be paid in any patients with a central nervous system disease. The clinical decision-making should be tailored to suit patients with ARN related to encephalitis, considering the extent and severity of the diseases and symptoms, as well as disease progression. Furthermore, consultation with a multidisciplinary team related to ophthalmology is highly recommended.\n\nAbbreviations\nARNAcute retinal necrosis\n\nHSVHerpes simplex virus\n\nBCVABest corrected visual acuity\n\nCSFCerebral spinal fluid\n\nRDRetinal detachment\n\nPCRPolymerase chain reaction\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nPingting Zhong and Siwen Zang contributed equally to this work.\n\nWe gratefully thank the patient and his parents for their kind participation in the study.\n\nAuthors’ contributions\nZ. PT and Z. SW wrote the manuscript, analyzed the data, and reviewed the literature. Y. HH performed the surgery. Z. PT and Z. SW collected ophthalmologic data and assisted in drafting the manuscript. Y. HH and Y. XH revised the manuscript and discussions. All authors read and approved the final manuscript.\n\nFunding\nThis work was supported by Science and Technology Program of Guangzhou, China (202002020049) (Y. XH); Project of Investigation on Health Status of Employees in Financial Industry in Guangzhou (Z012014075) (Y. XH).\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this article and are available from the corresponding author upon reasonable request.\n\nEthics approval and consent to participate\nThis study is a case report, the study design was approved by the ethics review board of the Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences. Written informed consent was obtained from the participant.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case and any accompanying images. This report does not contain any personal information that could lead to the identification of the patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Schoenberger SD Kim SJ Thorne JE Mruthyunjaya P Yeh S Bakri SJ Diagnosis and treatment of acute retinal necrosis: a report by the American Academy of ophthalmology Ophthalmology. 2017 124 3 382 392 10.1016/j.ophtha.2016.11.007. 28094044 \n2. Rochat C Polla BS Herbort CP Immunological profiles in patients with acute retinal necrosis Graefes Arch Clin Exp Ophthalmol 1996 234 9 547 552 10.1007/bf00448798. 8880152 \n3. Liang ZG Liu ZL Sun XW Tao ML Yu GP. Viral encephalitis complicated by acute retinal necrosis syndrome: a case report Exp Ther Med 2015 10 2 465 467 10.3892/etm.2015.2557. 26622338 \n4. Moon SM Kim T Lee EM Kang JK Lee SA Choi SH Comparison of clinical manifestations, outcomes and cerebrospinal fluid findings between herpes simplex type 1 and type 2 central nervous system infections in adults J Med Virol 2014 86 10 1766 1771 10.1002/jmv.23999 25042344 \n5. Broadhurst MJ Dujari S Budvytiene I Pinsky BA Gold CA Banaei N Utilization, yield, and accuracy of the FilmArray meningitis/encephalitis panel with diagnostic stewardship and testing algorithm J Clin Microbiol 2020 58 9 e00311 10.1128/jcm.00311-20 32493787 \n6. Vandercam T Hintzen RQ de Boer JH Van der Lelij A Herpetic encephalitis is a risk factor for acute retinal necrosis Neurology 2008 71 16 1268 1274 10.1212/01.wnl.0000327615.99124.99 18852442 \n7. Ogura H Fukae J Kimura S Aoki M Nabeshima K Nabeshima Y Acyclovir resistant acute herpes simplex encephalitis associated with acute retinal necrosis: a case report and review of the literature Rinsho Shinkeigaku 2017 57 5 230 233 10.5692/clinicalneurol.cn-000959. 28450685 \n8. Todokoro D Kamei S Goto H Ikeda Y Koyama H Akiyama H Acute retinal necrosis following herpes simplex encephalitis: a nationwide survey in Japan Jpn J Ophthalmol 2019 63 4 304 309 10.1007/s10384-019-00668-5. 31054049 \n9. Zhou C Zhu L Fang S Fulminant bilateral acute retinal necrosis syndrome associated with viral encephalitis: a case report Exp Ther Med 2016 12 4 2227 2229 10.3892/etm.2016.3594 27698716 \n10. Smith GA Gross SP Enquist LW Herpesviruses use bidirectional fast-axonal transport to spread in sensory neurons Proc Natl Acad Sci U S A 2001 98 6 3466 3470 10.1073/pnas.061029798 11248101 \n11. Kim SJ Kang SW Joo EY An unusual case of herpes simplex viral encephalitis following acute retinal necrosis after administration of a systemic steroid J Epilepsy Res 2012 2 1 21 24 10.14581/jer.12006 24649457 \n12. Tran TH Stanescu D Caspers-Velu L Rozenberg F Liesnard C Gaudric A Clinical characteristics of acute HSV-2 retinal necrosis Am J Ophthalmol 2004 137 5 872 879 10.1016/j.ajo.2003.12.036. 15126152 \n13. Labetoulle M Maillet S Efstathiou S Dezelee S Frau E Lafay F HSV1 latency sites after inoculation in the lip: assessment of their localization and connections to the eye Invest Ophthalmol Vis Sci 2003 44 1 217 225 10.1167/iovs.02-0464. 12506078 \n14. Kamei S Sekizawa T Shiota H Mizutani T Itoyama Y Takasu T Evaluation of combination therapy using aciclovir and corticosteroid in adult patients with herpes simplex virus encephalitis J Neurol Neurosurg Psychiatry 2005 76 11 1544 1549 10.1136/jnnp.2004.049676 16227548 \n15. Martinez-Torres F Menon S Pritsch M Victor N Jenetzky E Jensen K Protocol for German trial of acyclovir and corticosteroids in herpes-simplex-virus-encephalitis (GACHE): a multicenter, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial [ISRCTN45122933] BMC Neurol 2008 8 40 10.1186/1471-2377-8-40. 18959773 \n16. Hafidi M Janin-Manificat H Denis P Charleux B Rabilloud M Boibieux A Acute retinal necrosis: Virological features using quantitative polymerase chain reaction, therapeutic management, and clinical outcomes Am J Ophthalmol 2019 208 376 386 10.1016/j.ajo.2019.08.007. 31449790 \n17. Palay DA Sternberg P Davis J Lewis GN Mieler WF Jabs DA Decrease in the risk of bilateral acute retinal necrosis by acyclovir therapy Am J Ophthalmol 1991 112 3 250 255 10.1016/s0002-9394(14)76725-x 1882936 \n18. Lei B Jiang R Wang Z Xu G Xu X Zhou M Bilateral acute retinal necrosis: a case series Retina. 2020 40 1 145 153 10.1097/iae.0000000000002341. 30312259 \n19. Cochrane TF Silvestri G McDowell C Foot B McAvoy CE Acute retinal necrosis in the United Kingdom: results of a prospective surveillance study Eye 2012 26 3 370 377 10.1038/eye.2011.338 22281865 \n20. Fang CM Khan MA Mehta S Garg SJ Dunn JP Correlation of clinical outcomes with quantitative polymerase chain reaction DNA copy number in patients with acute retinal necrosis Ocul Immunol Inflamm 2017 25 2 246 252 10.3109/09273948.2015.1115081. 26828388\n\n",
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"title": "Herpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report.",
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"abstract": "Calcitonin gene-related peptide (CGRP) is involved in nociception and neurogenic inflammation in migraine, but also serves as a potent vasodilator acting on intracranial arteries. This latter effect raises concern about the possibility of drugs inhibiting CGRP precipitating cerebral ischemia. We describe a 41-year-old woman with migraine without aura who developed a right thalamic infarction following a first dose of erenumab, a CGRP-receptor blocker. Stroke onset occurred during a typical migraine. Imaging demonsrated right posterior cerebral artery near-occlusion initially with normalization of the vessel at follow-up imaging 2 months later, suggesting vasospasm as a possible mechanism. Extensive evaluation revealed no other specific cause of stroke or vascular risk factors aside from long-term use of oral contraceptive pills. CGRP inhibitors might be associated with ischemic stroke due to blockade of normal cerebral vasodilatory regulatory function.",
"affiliations": "Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: cucchiar@pennmedicine.upenn.edu.",
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"abstract": "Invasive primary squamous cell carcinomas involving the anorectal region are challenging to manage. Microsatellite instability has been shown to impact clinical courses and outcomes of patients affected by many types of carcinomas. To the best of our knowledge, there are no reports on microsatellite instability in anorectal squamous cell carcinomas. Here, we report a HPV-negative anorectal squamous cell carcinoma which, despite cisplatin-based chemoradiation therapy, showed progression. Interestingly, after identification of its mismatch repair-deficiency (MLH1/PMS2-absent, MSH2/MSH6-intact), pembrolizumab-based immunotherapy was initiated, leading to a marked clinical response. This unique case illustrates that microsatellite instability testing and immunotherapy targeting immune checkpoint blockade should be considered for managing anorectal squamous cell carcinomas that fail conventional chemoradiation therapies or when patients are non-surgical candidates. This report provides the first evidence of microsatellite instability in anorectal squamous cell carcinomas and supports the role for microsatellite instability testing in this cancer type to optimize patient management.",
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"authors": "Jiang|Kun|K|http://orcid.org/0000-0001-8531-7813;Martens|Brian|B|;Meyer|Logan|L|;Truong|Kim|K|;Lauwers|Gregory Y|GY|",
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"abstract": "In this case report, we present an evaluation of the distribution of postmortem concentrations of 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) in a fatality attributed principally to the drug. A man who had a history of drug abuse was found unresponsive and not breathing on his bed. Drug paraphernalia, indicating drug insufflation, was located in the decedent's room. Toxicology screening tests in peripheral blood initially identified U-47700 using an alkaline drug screen with gas chromatography-mass spectrometry (GC-MS) following solid-phase extraction. It was subsequently confirmed and quantitated by GC-MS-specific ion monitoring analysis following liquid-liquid extraction. The U-47700 peripheral blood concentration was quantitated at 190 ng/mL compared to the central blood concentration of 340 ng/mL. The liver concentration was 1,700 ng/g, the vitreous was 170 ng/mL, the urine was 360 ng/mL and the gastric contained only a trace amount (<1 mg). Other drugs detected in peripheral blood were alprazolam (0.12 mg/L), nordiazepam (<0.05 mg/L), doxylamine (0.30 mg/L), diphenhydramine (0.14 mg/L), ibuprofen (2.4 mg/L), salicylic acid (<20 mg/L) and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (2.4 ng/mL). The cause of death was certified as acute U-47700 and alprazolam abuse, and the manner of death was certified as accident.",
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"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000701:Analgesics, Opioid; D001344:Autopsy; D001549:Benzamides; D017809:Fatal Outcome; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D009293:Opioid-Related Disorders; D011180:Postmortem Changes; D014018:Tissue Distribution",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "158-160",
"pmc": null,
"pmid": "27798077",
"pubdate": "2017-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Fatality Related to the Synthetic Opioid U-47700: Postmortem Concentration Distribution.",
"title_normalized": "a fatality related to the synthetic opioid u 47700 postmortem concentration distribution"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-127529",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
... |
{
"abstract": "OBJECTIVE\nTo report that acute phenytoin toxicity may result in acute visual dysfunction.\n\n\nMETHODS\nA 19-year old man with cryptogenic simple partial and secondary generalized epilepsy developed blurred vision and xanthopsia after phenytoin loading for status epilepticus. Color blindness was found on testing with Ishihara's pseudo-isochromatic charts and visual fields (Goldmann perimeter) showed gross concentric constriction in both eyes. Flash visually evoked potentials showed prolonged P1 latency in both the eyes. Serum free-phenytoin concentration revealed toxic levels of phenytoin and no other etiology for retinopathy or optic neuropathy.\n\n\nRESULTS\nPhenytoin was withheld and the patient experienced a partial recovery in conjunction with reduced serum levels of phenytoin. Ten months later flash visually evoked potentials were normal but electroretinogram confirmed diffuse bilateral cone and rod dysfunction.\n\n\nCONCLUSIONS\nPhenytoin toxicity may result in acute visual dysfunction a previously unreported phenomenon.",
"affiliations": "Department of Ophthalmology, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman.",
"authors": "Thakral|Archana|A|;Shenoy|Radha|R|;Deleu|Dirk|D|",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-9009",
"issue": "103(4)",
"journal": "Acta neurologica Belgica",
"keywords": null,
"medline_ta": "Acta Neurol Belg",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D003118:Color Perception; D004827:Epilepsy; D005074:Evoked Potentials, Visual; D006801:Humans; D008297:Male; D009901:Optic Nerve Diseases; D010672:Phenytoin; D012160:Retina; D014786:Vision Disorders; D014794:Visual Fields",
"nlm_unique_id": "0247035",
"other_id": null,
"pages": "218-20",
"pmc": null,
"pmid": "15008507",
"pubdate": "2003-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute visual dysfunction following phenytoin-induced toxicity.",
"title_normalized": "acute visual dysfunction following phenytoin induced toxicity"
} | [
{
"companynumb": "OM-PFIZER INC-2014318079",
"fulfillexpeditecriteria": "1",
"occurcountry": "OM",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Angiosarcoma is a rare type of soft tissue sarcoma that accounts for less than 1% of all sarcomas and only 2% of all primary hepatic tumours. Thorotrast, arsenic, and vinyl chloride monomer are frequently listed as occupational exposure risks. The estimated latency is long (10-40 years) in occupational cases and very long (60 years or more) in non-occupational cases. The symptoms and CT-scan appearance of hepatic angiosarcoma (HAS) are non-specific. We present a case of a 65-year-old Caucasian male with history of cryptogenic cirrhosis, low alpha-foetoprotein levels and a single, 4-cm nodule of potential atypical hepatocellular carcinoma (no washout at MRI and CT-scan) in segment VIII. Laparoscopic radiofrequency ablation (a biopsy of the neoplastic lesion was technically impossible) was performed, followed by liver transplantation (LT) 6 months later. High-grade multifocal HAS was found in the explanted liver, with extensive involvement of the venous portal structures. No complications were observed during the postoperative course, and initial immunosuppression included tacrolimus, mycophenolate mofetil and corticosteroids. Because of the histological findings, tacrolimus was switched to everolimus as the main immunosuppressive drug one month after LT. Despite this conversion, the patient developed bone metastases 3 months after LT and peritoneal carcinosis one month later. This case report suggests that everolimus conversion does not inhibit the development of tumour metastases. Consequently, HAS remains an absolute contraindication to LT because of the poor outcome. If LT has been performed for incidental HAS, new molecular therapies (e.g. vascular endothelial growth factor antagonists) should be considered immediately after LT to improve the outcome.",
"affiliations": "Unité Médicale de Transplantation Hépatique, Hôpital Pitié-Salpétrière, AP-HP, 75013 Paris, France; Medicina Traslazionale, Università Piemonte Orientale Amedeo Avogrado, Novara, Italy.;Unité Médicale de Transplantation Hépatique, Hôpital Pitié-Salpétrière, AP-HP, 75013 Paris, France.;Service de Chirurgie Hépatobiliaire et Transplantation Hépatique, Hôpital Pitié-Salpétrière, AP-HP, 75013 Paris, France.;Service d'Anatomie et Cytologie Pathologique, Hôpital Pitié-Salpétrière, AP-HP, 75013 Paris, France.;Service de Chirurgie Hépatobiliaire et Transplantation Hépatique, Hôpital Pitié-Salpétrière, AP-HP, 75013 Paris, France.;Unité Médicale de Transplantation Hépatique, Hôpital Pitié-Salpétrière, AP-HP, 75013 Paris, France; UMR_S 938, CDR Saint-Antoine, Sorbonne Universités, UPMC Université Paris 06, 75005 Paris, France. Electronic address: filomena.conti@aphp.fr.",
"authors": "Tran Minh|M|M|;Mazzola|A|A|;Perdigao|F|F|;Charlotte|F|F|;Rousseau|G|G|;Conti|F|F|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.clinre.2017.02.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2210-7401",
"issue": "42(1)",
"journal": "Clinics and research in hepatology and gastroenterology",
"keywords": "Everolimus; Liver transplantation; Primary hepatic angiosarcoma",
"medline_ta": "Clin Res Hepatol Gastroenterol",
"mesh_terms": "D000368:Aged; D017809:Fatal Outcome; D006394:Hemangiosarcoma; D006801:Humans; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D016896:Treatment Outcome",
"nlm_unique_id": "101553659",
"other_id": null,
"pages": "17-23",
"pmc": null,
"pmid": "28416360",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary hepatic angiosarcoma and liver transplantation: Radiological, surgical, histological findings and clinical outcome.",
"title_normalized": "primary hepatic angiosarcoma and liver transplantation radiological surgical histological findings and clinical outcome"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1011883",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": n... |
{
"abstract": "We retrospectively examined the clinical characteristics, pathological features, and outcomes of BK viremia and nephropathy in a population of non-renal solid organ transplant patients (NRSOT) referred for outpatient nephrology consultation over a period of 5 years. In the entire cohort of liver, heart, and lung transplant recipients referred to this clinic, 14% percent were found to have BK viremia with a median peak serum BK viral load of 35 500 copies/ml (range 250 to 21 100 000 copies/ml). BK viremia resolved in six of the seventeen patients (35%). Four out of five patients biopsied showed BK virus (BKV) nephropathy. Eleven out of seventeen patients with BK viremia developed advanced (stage 4 or 5) chronic kidney disease. Four patients developed rejection of their solid organ transplant within the first year post detection of BK viremia after immunosuppression reduction. We conclude that a multi-center study is required to evaluate whether implementation of a systematic BK screening program would be effective in early detection and management of this problem in the NRSOT population.",
"affiliations": "Division of Transplant Nephrology, Augusta University-Medical College of Georgia, Augusta, GA, USA.;Division of Nephrology, Duke University School of Medicine, Durham, NC, USA.;Department of Pathology, Duke University School of Medicine, Durham, NC, USA.;Division of Nephrology, Duke University School of Medicine, Durham, NC, USA.",
"authors": "Mallavarapu|Ravi K|RK|0000-0003-4441-9279;Sanoff|Scott L|SL|;Howell|David N|DN|;Roberts|John K|JK|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.14265",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "35(5)",
"journal": "Clinical transplantation",
"keywords": "BK virus; immunosuppression; renal failure; solid organ transplant",
"medline_ta": "Clin Transplant",
"mesh_terms": "D001739:BK Virus; D006801:Humans; D016377:Organ Transplantation; D027601:Polyomavirus Infections; D012189:Retrospective Studies; D066027:Transplant Recipients; D014412:Tumor Virus Infections",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "e14265",
"pmc": null,
"pmid": "33615555",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "BK virus nephropathy in non-renal solid organ transplant recipients: Are we looking hard enough?",
"title_normalized": "bk virus nephropathy in non renal solid organ transplant recipients are we looking hard enough"
} | [
{
"companynumb": "NVSC2021US079839",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "Nevirapine (NVP) resistance occurs frequently in infants following NVP use in prevention of mother-to-child transmission (PMTCT) regimens. However, among previously NVP-unexposed infants treated with NVP-antiretroviral therapy (ART), the development and impact of NVP resistance have not been well characterized. In a prospective clinical trial providing early ART to HIV-infected infants <5 months of age in Kenya (OPH03 study), we followed NVP-unexposed infants who initiated NVP-ART for 12 months. Viral loads were assessed and resistance determined using a population-based genotypic resistance assay. Of 99 infants screened, 33 had no prior NVP exposure, 22 of whom were initiated on NVP-ART. Among 19 infants with follow-up, seven (37%) infants developed resistance: one at 3 months and six at 6 months after ART initiation. The cumulative probability of NVP resistance was 5.9% at 3 months and 43.5% at 6 months. Baseline HIV RNA levels (p=0.7) and other characteristics were not associated with developing resistance. Post-ART, higher virus levels at visits preceding the detection of resistance were significantly associated with increased detection of resistance (p=0.004). Virus levels after 6 and 12 months of ART were significantly higher in infants with resistance than those without (p=0.007, p=0.030, respectively). Among infants without previous NVP exposure, development of NVP resistance was frequent and was associated with virologic failure during the first year of ART. Earlier development of NVP resistance in infants than in adults initiating NVP-ART may be due to longer viremia following ART or inadequate NVP levels resulting from NVP lead-in dosing. The development of NVP resistance may, in part, explain the superiority of protease inhibitor-based ART in infants.",
"affiliations": "1 Department of Medical Microbiology, University of Nairobi , Nairobi, Kenya .;2 Department of Global Health, University of Washington , Seattle, Washington.;2 Department of Global Health, University of Washington , Seattle, Washington.;4 Department of Pediatrics, University of Nairobi , Nairobi, Kenya .;3 Kenya Medical Research Institute , Nairobi, Kenya .;4 Department of Pediatrics, University of Nairobi , Nairobi, Kenya .;4 Department of Pediatrics, University of Nairobi , Nairobi, Kenya .;5 Fred Hutchinson Cancer Research Center , Seattle, Washington.;2 Department of Global Health, University of Washington , Seattle, Washington.",
"authors": "Chohan|Bhavna H|BH|;Tapia|Kenneth|K|;Benki-Nugent|Sarah|S|;Khasimwa|Brian|B|;Ngayo|Musa|M|;Maleche-Obimbo|Elizabeth|E|;Wamalwa|Dalton|D|;Overbaugh|Julie|J|;John-Stewart|Grace|G|",
"chemical_list": "D044966:Anti-Retroviral Agents; D019829:Nevirapine",
"country": "United States",
"delete": false,
"doi": "10.1089/AID.2014.0370",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0889-2229",
"issue": "31(8)",
"journal": "AIDS research and human retroviruses",
"keywords": null,
"medline_ta": "AIDS Res Hum Retroviruses",
"mesh_terms": "D044966:Anti-Retroviral Agents; D023241:Antiretroviral Therapy, Highly Active; D024882:Drug Resistance, Viral; D005260:Female; D060005:Genotyping Techniques; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007223:Infant; D007630:Kenya; D008137:Longitudinal Studies; D008297:Male; D020125:Mutation, Missense; D019829:Nevirapine; D011446:Prospective Studies; D055502:Secondary Prevention; D013997:Time Factors; D019562:Viral Load",
"nlm_unique_id": "8709376",
"other_id": null,
"pages": "783-91",
"pmc": null,
"pmid": "25819584",
"pubdate": "2015-08",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "24849473;24326597;12768032;15075541;9847340;9889216;15937769;16511413;16709991;16810119;17414406;19020325;19194272;19502990;20868279;21332984;21288774;21500872;22544051;22716976;22719231;22581223;10878065",
"title": "Nevirapine Resistance in Previously Nevirapine-Unexposed HIV-1-Infected Kenyan Infants Initiating Early Antiretroviral Therapy.",
"title_normalized": "nevirapine resistance in previously nevirapine unexposed hiv 1 infected kenyan infants initiating early antiretroviral therapy"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US05416",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "Mud runs are an increasingly popular recreational fitness activity across the United States, combining a running race through an obstacle course with submersion in mud. Recent reports estimate 4 million people have participated in these types of events over the last 5 years. We describe an atypical case of myocarditis and multiorgan failure from disseminated histoplasmosis in a previously healthy pediatric patient, likely acquired during participation in a mud run. Although cases of histoplasmosis-associated endocarditis and pericarditis have been reported in the literature, cases of histoplasmosis myocarditis are rare.",
"affiliations": "Department of Pediatrics, Duke Children's Hospital and Health Center, Durham, North Carolina briana.l.scott@duke.edu.;Department of Pediatrics, Duke Children's Hospital and Health Center, Durham, North Carolina.;Department of Pediatrics, Duke Children's Hospital and Health Center, Durham, North Carolina.;Department of Pediatrics, Duke Children's Hospital and Health Center, Durham, North Carolina.;Department of Pediatrics, Duke Children's Hospital and Health Center, Durham, North Carolina.",
"authors": "Scott|Briana L|BL|;Sherwin|Jennifer I|JI|;Rehder|Kyle J|KJ|;Campbell|Michael J|MJ|;Ozment|Caroline P|CP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2017-1074",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "141(Suppl 5)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000293:Adolescent; D019353:Endemic Diseases; D005260:Female; D006660:Histoplasmosis; D006801:Humans; D007121:Immunocompetence; D009102:Multiple Organ Failure; D009205:Myocarditis; D009657:North Carolina; D012420:Running; D012988:Soil Microbiology",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "S462-S465",
"pmc": null,
"pmid": "29610172",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Histoplasmosis Myocarditis in an Immunocompetent Host After a Recreational Mud Run.",
"title_normalized": "histoplasmosis myocarditis in an immunocompetent host after a recreational mud run"
} | [
{
"companynumb": "US-009507513-1804USA010730",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "POSACONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Literature regarding the anesthetic care of patients with scleroderma during labor and delivery is limited to remote case reports. No recent publications provide information on the anesthetic management of patients with coexisting pulmonary hypertension. This report describes the anesthetic and multidisciplinary management of two pregnant patients with concomitant scleroderma and pulmonary hypertension undergoing cesarean delivery; one with neuraxial anesthesia and one with general anesthesia. Considerations for neuraxial and general anesthesia in patients with concurrent scleroderma and pulmonary hypertension are discussed.",
"affiliations": "University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA. Electronic address: dmoaveni@med.miami.edu.;University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA.;University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA.;University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA.;University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA.",
"authors": "Moaveni|D|D|;Cohn|J|J|;Brodt|J|J|;Hoctor|K|K|;Ranasinghe|J|J|",
"chemical_list": "D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D000779:Anesthetics, Local; D000959:Antihypertensive Agents; D008738:Methyl Ethers; D000077149:Sevoflurane; D011464:Epoprostenol; D005283:Fentanyl; D002045:Bupivacaine",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-289X",
"issue": "24(4)",
"journal": "International journal of obstetric anesthesia",
"keywords": "Anesthesia; CREST syndrome; Cesarean delivery; Epoprostenol; Obstetric; Pulmonary hypertension; Scleroderma",
"medline_ta": "Int J Obstet Anesth",
"mesh_terms": "D000328:Adult; D000767:Anesthesia, Epidural; D000768:Anesthesia, General; D000773:Anesthesia, Obstetrical; D000775:Anesthesia, Spinal; D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D000779:Anesthetics, Local; D000959:Antihypertensive Agents; D002045:Bupivacaine; D002585:Cesarean Section; D011464:Epoprostenol; D005260:Female; D005283:Fentanyl; D006801:Humans; D006976:Hypertension, Pulmonary; D008738:Methyl Ethers; D011247:Pregnancy; D011248:Pregnancy Complications; D012595:Scleroderma, Systemic; D000077149:Sevoflurane; D055815:Young Adult",
"nlm_unique_id": "9200430",
"other_id": null,
"pages": "375-82",
"pmc": null,
"pmid": "26119257",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Scleroderma and pulmonary hypertension complicating two pregnancies: use of neuraxial anesthesia, general anesthesia, epoprostenol and a multidisciplinary approach for cesarean delivery.",
"title_normalized": "scleroderma and pulmonary hypertension complicating two pregnancies use of neuraxial anesthesia general anesthesia epoprostenol and a multidisciplinary approach for cesarean delivery"
} | [
{
"companynumb": "US-ACTELION-A-CH2015-126416",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nDespite vancomycin being in use for over half-a-century, it is still not dosed or monitored appropriately in many centers around the world. The objective of this study was to determine the effectiveness of a multifaceted intervention to implement a vancomycin dosing and monitoring guideline across multiple medical and surgical units over time.\n\n\nMETHODS\nThis was an observational before-and-after interventional cohort study. The pre-intervention period was August to December 2010-2011 and the post-intervention period was September to November 2012-2014. The implementation strategy comprised: face-to-face education, online continuing medical education, dissemination of pocket guideline and email reminder. Outcome measures included: appropriate prescribing of loading and maintenance doses, therapeutic drug monitoring, time to attain target range and nephrotoxicity.\n\n\nRESULTS\nPost-implementation prescribing of loading doses increased (10.4%-43.6%, P=<0.001), guideline adherent first maintenance dose (44%-68.4% P = 0.04), correct dose adjustment from (53.1%-72.2%, P = 0.009). Beneficial effects pre and post-implementation were observed for adherent timing of initial concentration (43.2%-51.9%, P = 0.01), concentrations in target range (32.6%-44.1%, P = 0.001), time to target range (median 6-4 days, P=<0.001), potentially nephrotoxic concentrations (30.7%-20.9%, P=<0.001) and nephrotoxicity (10.4%-6.8%, P=<0.001).\n\n\nCONCLUSIONS\nA multifaceted intervention to implement a vancomycin dosing and monitoring guideline significantly improved prescribing, monitoring, pharmacokinetic and safety outcomes for patients treated with vancomycin over an extended period. However, increased guideline adoption by clinicians is required to maximize and prolong the utility of this important agent.",
"affiliations": "SA Pharmacy, Flinders Medical Centre, Bedford Park, SA, 5042, Australia; Department of Microbiology and Infectious Diseases, School of Medicine, Flinders University, Adelaide, SA, 5000, Australia; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia. Electronic address: cameron.phillips@sa.gov.au.;School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia; Flinders Centre for Innovation in Cancer, Flinders University, Adelaide, SA, 5000, Australia. Electronic address: ross.mcKinnon@flinders.edu.au.;Flinders Centre for Epidemiology and Biostatistics, School of Medicine, Flinders University, Adelaide, SA, 5000, Australia. Electronic address: richard.woodman@flinders.edu.au.;Department of Microbiology and Infectious Diseases, School of Medicine, Flinders University, Adelaide, SA, 5000, Australia; SA Pathology, Microbiology and Infectious Diseases, Flinders Medical Centre, Bedford Park, SA 5042, Australia; Division of Medicine, Flinders Medical Centre, Bedford Park, SA, 5042, Australia. Electronic address: d.gordon@flinders.edu.au.",
"authors": "Phillips|Cameron J|CJ|;McKinnon|Ross A|RA|;Woodman|Richard J|RJ|;Gordon|David L|DL|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2017.09.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "24(2)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Education; Guideline; Intervention; Therapeutic drug monitoring; Vancomycin",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000046:Academic Medical Centers; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001315:Australia; D015331:Cohort Studies; D016903:Drug Monitoring; D005260:Female; D005500:Follow-Up Studies; D019983:Guideline Adherence; D006784:Hospitals, Teaching; D006801:Humans; D008297:Male; D008875:Middle Aged; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus; D014640:Vancomycin",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "103-109",
"pmc": null,
"pmid": "29037461",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Sustained improvement in vancomycin dosing and monitoring post-implementation of guidelines: Results of a three-year follow-up after a multifaceted intervention in an Australian teaching hospital.",
"title_normalized": "sustained improvement in vancomycin dosing and monitoring post implementation of guidelines results of a three year follow up after a multifaceted intervention in an australian teaching hospital"
} | [
{
"companynumb": "AU-PENTEC HEALTH-2018PEN00016",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN HYDROCHLORIDE"
},
"drugadditio... |
{
"abstract": "A 40-year-old man with chronic history of refractory palmoplantar psoriasis presented with new onset of well-demarcated oval erythematous asteatotic plaques on bilateral shins after starting guselkumab therapy. Histopathology revealed chronic spongiotic dermatitis consistent with a diagnosis of nummular dermatitis. This case highlights a previously unreported adverse event to guselkumab therapy.",
"affiliations": "Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.;Department of Dermatology, University of California Davis School of Medicine, Sacramento, California.;Department of Dermatology, University of California Davis School of Medicine, Sacramento, California.;Department of Dermatology, University of California Davis School of Medicine, Sacramento, California.",
"authors": "Truong|Allison|A|;Le|Stephanie|S|0000-0001-5142-7010;Kiuru|Maija|M|;Maverakis|Emanual|E|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D003879:Dermatologic Agents; C000588857:guselkumab",
"country": "United States",
"delete": false,
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"journal": "Dermatologic therapy",
"keywords": "IL23; Th17; dermatitis; guselkumab; nummular; palmoplantar; psoriasis",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D003879:Dermatologic Agents; D003875:Drug Eruptions; D006801:Humans; D008297:Male; D011565:Psoriasis",
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"title": "Nummular dermatitis on guselkumab for palmoplantar psoriasis.",
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"abstract": "Antidepressant drugs are reported to cause alterations in blood glucose homeostasis in adults with diabetes mellitus. We report a patient with persistent congenital hyperinsulinism (CHI) who developed recurrent hypoglycaemia following fluoxetine therapy. This 15-year-old girl was initially managed with diazoxide therapy. She developed troublesome hypertrichosis, which affected her quality of life adversely. Diazoxide was then slowly weaned and stopped with the introduction of octreotide, to which she responded well. Subcutaneous lanreotide (long-acting somatostatin analogue) was subsequently commenced (30 mg, once monthly) as injecting octreotide multiple times a day was proving to be difficult for the patient. The continuous blood glucose monitoring on monthly lanreotide injections revealed good glycaemic control. Six months later, she developed depression due to psychosocial problems at school. She was started on fluoxetine by the psychiatry team. She subsequently developed recurrent symptomatic hypoglycaemic episodes (blood glucose <3.5 mmol/L) and fluoxetine was discontinued, following which the hypoglycaemic episodes resolved within a week. Fluoxetine has been associated with hypoglycaemia in patients with diabetes mellitus. We report, for the first time, hypoglycaemia secondary to fluoxetine in a patient with CHI.",
"affiliations": "Alder Hey Children's Hospital, Clinic of Pediatric Endocrinology, Liverpool, United Kingdom, Phone: +44 1512525281 E-mail: senthilkss@yahoo.co.uk.",
"authors": "Giri|Dinesh|D|;Price|Victoria|V|;Yung|Zoe|Z|;Didi|Mohammed|M|;Senniappan|Senthil|S|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; D005473:Fluoxetine; C060347:lanreotide; D013004:Somatostatin",
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"fulltext": "\n==== Front\nJ Clin Res Pediatr EndocrinolJ Clin Res Pediatr EndocrinolJCRPEJournal of Clinical Research in Pediatric Endocrinology1308-57271308-5735Galenos Publishing 2708726410.4274/jcrpe.28181790Case ReportFluoxetine-Induced Hypoglycaemia in a Patient with Congenital Hyperinsulinism on Lanreotide Therapy Giri Dinesh 1Price Victoria 1Yung Zoe 1Didi Mohammed 1Senniappan Senthil 1*1 \nAlder Hey Children’s Hospital, Clinic of Pediatric Endocrinology, Liverpool, United Kingdom\n* Address for Correspondence: Alder Hey Children’s Hospital, Clinic of Pediatric Endocrinology, Liverpool, United Kingdom Phone: +44 1512525281 E-mail: senthilkss@yahoo.co.uk9 2016 1 9 2016 8 3 347 350 6 1 2016 27 2 2016 © Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.2016This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Antidepressant drugs are reported to cause alterations in blood glucose homeostasis in adults with diabetes mellitus. We report a patient with persistent congenital hyperinsulinism (CHI) who developed recurrent hypoglycaemia following fluoxetine therapy. This 15-year-old girl was initially managed with diazoxide therapy. She developed troublesome hypertrichosis, which affected her quality of life adversely. Diazoxide was then slowly weaned and stopped with the introduction of octreotide, to which she responded well. Subcutaneous lanreotide (long-acting somatostatin analogue) was subsequently commenced (30 mg, once monthly) as injecting octreotide multiple times a day was proving to be difficult for the patient. The continuous blood glucose monitoring on monthly lanreotide injections revealed good glycaemic control. Six months later, she developed depression due to psychosocial problems at school. She was started on fluoxetine by the psychiatry team. She subsequently developed recurrent symptomatic hypoglycaemic episodes (blood glucose <3.5 mmol/L) and fluoxetine was discontinued, following which the hypoglycaemic episodes resolved within a week. Fluoxetine has been associated with hypoglycaemia in patients with diabetes mellitus. We report, for the first time, hypoglycaemia secondary to fluoxetine in a patient with CHI.\n\nFluoxetineselective serotonin reuptake inhibitorhypoglycaemiaHyperinsulinism\n==== Body\nWHAT IS ALREADY KNOWN ON THIS TOPIC?\nDiazoxide is used as the first-line medication in congenital hyperinsulinism (CHI). Troublesome hypertrichosis may occur as a side-effect which may lead to depression, particularly in adolescent females. Fluoxetine, an antidepressant, has been implicated to cause disturbances in glucose homeostasis in patients with diabetes.\n\nWHAT THIS STUDY ADDS?\nFluoxetine can cause or worsen hypoglycaemia in patients with CHI. This has not been reported in the literature before.\n\nINTRODUCTION\nCongenital hyperinsulinism (CHI) is a disorder caused by dysregulated insulin secretion from the beta cells of the pancreas and is the major cause of hypoglycaemia during infancy and childhood (1). Antidepressant agents have been implicated to contribute to glucose dysregulation, causing both hypo- and hyperglycemia, depending on the specific medication used (2). Such disturbances have been reported in normal subjects as well as in patients with diabetes mellitus (DM). Selective serotonin reuptake inhibitors (SSRIs), in particular fluoxetine, have been associated with hypoglycaemia, reduced awareness of hypoglycaemic episodes, and increased insulin sensitivity in patients with DM (3,4,5,6,7). It is well known that unrecognised and untreated hypoglycaemia can be devastating and can potentially cause neurological damage. Moreover, the hypoglycaemic episodes occurring as a side-effect of these medications can have a negative psychological impact in a chronic condition such as DM and persistent forms of CHI. It is therefore important to be aware of the potential impact of antidepressants on glycaemic control in patients with DM and CHI. Fluoxetine-induced hypoglycaemia has been reported in the literature in adult patients with DM with paucity of literature in the paediatric population. Also, to our knowledge, there are no previous published report of fluoxetine-induced hypoglycaemia in patients with CHI. We report a 15-year-old girl with CHI who developed persistent and recurrent hypoglycaemia secondary to fluoxetine.\n\nCASE REPORT\nA 15-year-old girl with a diagnosis of CHI was referred to our clinic from a District General Hospital. She was born to healthy non-consanguineous Caucasian parents. She was noted to be hypoglycemic since birth and subsequent diagnostic work up for hypoglycaemia led to the diagnosis of CHI. CHI was defined as an inappropriately elevated insulin level (100 pmol/L) during hypoglycaemia (2 mmol/L) with suppressed fatty acids (<100 µmol/L) and 3-hydroxy butyrate (<100 µmol/L). Genetic analysis of the patient revealed a de novo heterozygous ABCC8 mutation. She was started on diazoxide (5 mg/kg/day), in conjunction with chlorothiazide (7 mg/kg/day), to which she responded well. Chlorothiazide was subsequently weaned and stopped when the patient was 5 years of age. At this time, 18-Fluro DOPA positron emission tomography (PET) computed tomography scan of the pancreas revealed diffuse disease. While glycemic control was optimal on diazoxide, its long-term use caused hypertrichosis, a well-known side effect of the drug. The troublesome hypertrichosis continued through her teenage years and had a significant impact on her quality of life. She suffered from depression and was missing a lot of school. She was referred for therapies including wax therapy and laser to help with her hirsutism. Unfortunately, the hypertrichosis and hirsutism were not amenable to these therapies. This was imposing a negative impact on her quality of life with her committing deliberate self-harm on a few occasions. The patient was in continuous need for psychological assistance and support. She was electively admitted to our pediatric inpatient unit to decide on an alternative medical treatment for CHI. A trial off diazoxide was performed whereby, diazoxide was gradually weaned and stopped for 72 hours. However, this led to subsequent development of recurrent symptomatic hypoglycaemia (blood glucose <3.5 mmol/L). Further investigations revealed a persistent hyperinsulinaemic hypoglycaemia with a plasma insulin concentration of 96 pmol/L and a suppressed plasma ketone level (free fatty acids-608 µmol/L, 3 hydroxy butyrate-47 µmol/L) when the plasma blood glucose was 2.6 mmol/L. Octreotide (a somatostatin analogue) was then commenced as four times daily subcutaneous injection. Baseline investigations including ultrasound of gall bladder, thyroid function tests, and insulin-like growth factor-1 (IGF1) level prior to commencement of octreotide were within normal limits. Octreotide was started at 5 mcg/kg/day and was gradually built up to 15 mcg/kg/day as 4 divided subcutaneous injections. A good glycemic response was noted at this dose and she was able to tolerate a fast for a period of 24 hours with no evidence of hypoglycaemia. However, a 4 times daily injection therapy was becoming too labour intense for her and she did not tolerate this intense therapy. Hence, lanreotide (long-acting somatostatin analogue) was commenced as a subcutaneous injection 30 mg once monthly and octreotide was gradually weaned and stopped. The continuous blood glucose monitoring system following the administration of lanreotide revealed good glycaemic control with no episodes of hypoglycaemia. She also noted significant improvement in her quality of life and her school attendance improved.\n\nSix months later, she developed depression due to psychosocial problems at school. She was assessed by a psychiatrist and was commenced on fluoxetine at a dose of 20 mg once daily. A week later, after the commencement of fluoxetine, the patient developed recurrent symptomatic hypoglycaemic episodes (blood glucose <3.5 mmol/L). The blood test during one of these hypoglycaemic episodes showed suppressed plasma insulin (<14 pmol/L) and c-peptide (<100 pmol/L) concentrations. Continuous blood glucose monitoring (CGM) was performed while the patient was on fluoxetine. The CGM did reveal multiple hypoglycaemic episodes (blood glucose <3.5 mmol/L) (Figure 1). After discussing with the psychiatric team, fluoxetine was discontinued, following which the hypoglycaemic episodes resolved within a week. CGM, two weeks after the discontinuation of fluoxetine, revealed a resolution of the hypoglycaemic episodes (Figure 2). The patient’s depressive symptoms slowly improved over time with the help of counselling.\n\nDISCUSSION\nPersistent CHI and DM are chronic medical conditions that cause disturbances in glucose homeostasis. DM is one of the commonest chronic diseases in childhood. Hypoglycaemia is a common occurrence in both these conditions. Moreover, chronic illnesses usually carry the risk of associated depression. For instance, in adults with DM, the risk of co-morbid depression is 8.5% to 20.0% higher than the general population (8). Treatment of depression associated with chronic illness is important as delay or non-treatment may lead to poor glycaemic control. For instance, in patients with DM, depression is associated with hyperglycaemia and an increased risk for diabetic complications and treatment of depression is associated with improved glycaemic control (9). In our patient, the extent of psychosocial problems at her school was affecting her adversely and warranted the need for psychiatric counselling and antidepressant therapy.\n\nSSRIs are one of the most commonly used antidepressant medications and are usually the first choice for depression because of fewer side effects than most other types of antidepressants (10). Fluoxetine, an SSRI, is an antidepressant that leads to enhanced serotonergic neurotransmission. Fluoxetine blocks serotonin reuptake and increases serotonin stimulation of receptors during the acute phase, and chronic use leads to desensitization of somatodendritic 5-HT1A and of terminal autoreceptors with an overall clinical effect of increased mood and decreased anxiety (11). Fluoxetine is indicated for use in pediatric patients over 8 years of age with multiple mental health diagnoses, including depression. It is a daily oral tablet, which can be titrated according to effect (12).\n\nIn our patient, diazoxide was providing optimal management for hypoglycaemia but due to significant hypertrichosis interfering with lifestyle and not amenable to therapies, octreotide was introduced which proved to be effective. As octreotide involves multiple injections which were proving to be difficult for the patient, lanreotide (long-acting somatostatin analogue, 30 mg as subcutaneous injection, once a month) was introduced and was providing optimal glycaemic control (13), until our patient developed hypoglycaemic episodes following fluoxetine therapy.\n\nAntidepressant drugs, particularly SSRIs, are reported to have a variety of effects on glucose homeostasis. SSRIs may cause hypoglycaemic unawareness secondary to autonomic dysfunction (14). Various mechanisms have been hypothesised to explain fluoxetine-induced hypoglycaemia. PET in healthy subjects has shown a decrease in the relative cerebral glucose metabolism in the amygdaloid complex, hippocampal formation, and ventral striatum with fluoxetine when compared to a placebo (15). McIntyre et al (2) suggested a central mechanism of action of fluoxetine. Potter van Loon et al (7) have shown that fluoxetine improves peripheral and hepatic insulin action in obese insulin-resistant subjects irrespective of its weight lowering effect. In a randomized, double-blind, placebo-controlled trial, insulin-mediated glucose disposal was measured in 12 obese patients with non-insulin dependent DM (NIDDM) on diet alone before and after four weeks of treatment with either placebo or fluoxetine and it was found that fluoxetine improves insulin-mediated glucose disposal in obese patients with NIDDM (6). These studies suggest that fluoxetine may have a role in increasing the insulin sensitivity. In our patient with CHI, a condition that causes an excessive and dysregulated insulin secretion, we believe that the introduction of fluoxetine has caused an increase in insulin sensitivity thereby resulting in recurrent hypoglycaemic episodes. Resolution of the hypoglycaemic episodes two weeks after stopping of fluoxetine substantiates this hypothesis.\n\nIn conclusion, this case demonstrates that hypertrichosis, a common side effect of diazoxide therapy for CHI, can result in depression, particularly in adolescent females. Management of diazoxide-responsive patients using long-acting somatostatin analogue, lanreotide, might be beneficial both in terms of increasing the patient’s compliance and avoiding the side effects which usually constitutes the main concern for families and patients. Although fluoxetine-related hypoglycaemia has been reported in patients with DM, it may not be a widely recognized phenomenon among many health professionals. We report, for the first time, hypoglycaemia secondary to fluoxetine in a patient with CHI. We suggest that close blood glucose monitoring should be undertaken in patients with disorders of glucose homeostasis who are commenced on antidepressant therapy.\n\nEthics\nInformed Consent: It was taken.\n\nPeer-review: Externally peer-reviewed.\n\nConcept: Dinesh Giri, Senthil Senniappan, Victoria Price, Mohammed Didi, Zoe Yung, Design: Dinesh Giri, Senthil Senniappan, Victoria Price, Mohammed Didi, Data Collection or Processing: Dinesh Giri, Zoe Yung, Analysis or Interpretation: Dinesh Giri, Zoe Yung, Senthil Senniappan, Literature Research: Dinesh Giri, Victoria Price, Senthil Senniappan, Writing: Dinesh Giri, Victoria Price, Senthil Senniappan.\n\nFinancial Disclosure: The authors declared that this study received no financial support.\n\nFigure 1 Continuous blood glucose monitoring on fluoxetine\nFigure 2 Continuous blood glucose monitoring off fluoxetine\n==== Refs\nReferences\n1 Senniappan S Shanti B James C Hussain K J Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management Inherit Metab Dis 2012 35 589 601 \n2 McIntyre RS Soczynska JK Konarski JZ Kennedy SH The effect of antidepressants on glucose homeostasis and insulin sensitivity: synthesis and mechanisms Expert Opin Drug Saf 2006 5 157 168 16370964 \n3 Deeg MA Lipkin EW Hypoglycemia associated with the use of fluoxetine West j Med 1996 164 262 263 8775944 \n4 Khoza S Barner JC Glucose dysregulation associated with antidepressant agents: an analysis of 17 published case reports Int J Clin Pharm 2011 13 484 492 \n5 Sawka AM Burgart V Zimmerman D Loss of hypoglycaemia awareness in an adolescent with type 1 diabetes mellitus during treatment with fluoxetine hydrochloride J Pediatr 2000 136 394 396 10700699 \n6 Maheux P Ducros F Bourque J Garon J Chiasson JL Fluoxetine improves insulin sensitivity in obese patients with non-insulin-dependent diabetes mellitus independently of weight loss Int J Obes Relat Metab Disord 1997 21 97 102 9043962 \n7 Potter -Loon BJ Radder JK Frölich M Krans HM Zwinderman AH Meinders AE Fluoxetine increases insulin action in obese type II (non-insulin dependent) diabetic patients Int J Obes Relat Metab Disord 1992 16(Suppl 4) 55 61 \n8 Ali S Stone MA Peters JL Davies MJ Khunti K The prevalence of co-morbid depression in adults with Type 2 diabetes: a systematic review and meta-analysis Diabet Med 2006 23 1165 1173 17054590 \n9 Anderson RJ Freedland KE Clouse RE Lustman PJ The prevalence of comorbid depression in adults with diabetes: a meta-analysis Diabetes Care 2001 24 1069 1078 11375373 \n10 [Internet] http://www.nhs.uk/conditions/ssris-(selective-serotonin-reuptake inhibitors)/pages/introduction.aspx \n11 [Internet] http://www.drugbank.ca/drugs/DB00472 \n12 [Internet] https://www.evidence.nhs.uk/formulary/bnfc/current/4-central-nervous-system/43-antidepressant-drugs/433-selective-serotonin-re-uptake-inhibitors/fluoxetine \n13 Modan-Moses D Koren I Mazor-Aronovitch K Pinhas-Hamiel O Landau H Treatment of congenital hyperinsulinism with lanreotide acetate (Somatuline Autogel) Clin Endocrinol Metab 2011 96 2312 2317 \n14 Sawka AM Burgart V Zimmerman D Loss of awareness of hypoglycemia temporally associated with selective serotonin reuptake inhibitors Diabetes Care 2001 24 1845 1846 11574457 \n15 Cook EH Jr Metz J Leventhal BL Lebovitz M Nathan M Semerdjian SA Brown T Cooper MD Fluoxetine effects on cerebral glucose metabolism Neuroreport 1994 5 1745 1748 7827322\n\n",
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"mesh_terms": "D000293:Adolescent; D018687:Antidepressive Agents, Second-Generation; D000970:Antineoplastic Agents; D044903:Congenital Hyperinsulinism; D003863:Depression; D005260:Female; D005473:Fluoxetine; D006801:Humans; D007003:Hypoglycemia; D010456:Peptides, Cyclic; D013004:Somatostatin",
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"other_id": null,
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"title": "Fluoxetine-Induced Hypoglycaemia in a Patient with Congenital Hyperinsulinism on Lanreotide Therapy.",
"title_normalized": "fluoxetine induced hypoglycaemia in a patient with congenital hyperinsulinism on lanreotide therapy"
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"abstract": "Vanishing bile duct syndrome (VBDS) is a rare disorder characterized by loss of interlobular bile ducts and progressive worsening cholestasis. The acute presentation of this disease is typically associated with a drug hypersensitivity and Stevens-Johnson syndrome/toxic epidermal necrolysis (TEN). The mainstay of treatment has been ursodeoxycholic acid with mixed results from immunosuppressive regimens. Anti-tumor necrosis factor-α and plasmapheresis have been speculated to be of potential benefit. It is hoped that early identification and intervention in VBDS secondary to Stevens-Johnson syndrome/TEN with continued reporting will lead to better regimens and outcomes. Our case report details the first reported use of infliximab and plasmapheresis, in addition to steroids, in a patient with VBDS secondary to TEN, as well as a literature review that supports a mechanism for why these modalities could be effective treatments. Unfortunately, our patient died, and the use of these therapies had an unclear benefit on his liver and skin disease. We hope that additional work can be published to confirm or refute their utility in the treatment of these diseases.",
"affiliations": "Pediatric Residency Program, and.;Section of Gastroenterology, Department of Pediatrics, St Christopher's Hospital for Children, Philadelphia, Pennsylvania stephanie.appleman@tenethealth.com.",
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"issue": "134(4)",
"journal": "Pediatrics",
"keywords": "Stephens-Johnson syndrome; TNF-α inhibitor; plasmapheresis; toxic epidermal necrolysis; vanishing bile duct",
"medline_ta": "Pediatrics",
"mesh_terms": "D000911:Antibodies, Monoclonal; D001649:Bile Duct Diseases; D001652:Bile Ducts; D002648:Child; D006801:Humans; D000069285:Infliximab; D008297:Male; D010956:Plasmapheresis; D013262:Stevens-Johnson Syndrome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0376422",
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"title": "Infliximab/Plasmapheresis in vanishing bile duct syndrome secondary to toxic epidermal necrolysis.",
"title_normalized": "infliximab plasmapheresis in vanishing bile duct syndrome secondary to toxic epidermal necrolysis"
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"abstract": "Flow diversion for basilar apex aneurysms has rarely been reported.\n\n\n\nTo assess flow diversion for basilar apex aneurysms in a multicenter cohort.\n\n\n\nRetrospective review of prospectively maintained databases at 8 academic institutions was performed from 2009 to 2016 to identify patients with basilar apex aneurysms treated with flow diversion. Clinical and radiographic data were analyzed.\n\n\n\nSixteen consecutive patients (median age 54.5 yr) underwent 18 procedures to treat 16 basilar apex aneurysms with either the Pipeline Embolization Device (Medtronic Inc, Dublin, Ireland) or Flow Redirection Endoluminal Device (Microvention, Tustin, California). Five aneurysms (31.3%) were treated in the setting of subarachnoid hemorrhage. Seven aneurysms (43.8%) were treated with flow diversion alone, while 9 (56.2%) underwent flow diversion and adjunctive coiling. At a median follow-up of 6 mo, complete (100%) and near-complete (90%-99%) occlusion was noted in 11 (68.8%) aneurysms. Incomplete occlusion occurred more commonly in patients treated with flow diversion alone compared to those with adjunctive coiling. Patients with partial occlusion were significantly younger. Retreatment with an additional flow diverter and adjunctive coiling occurred in 2 aneurysms with wide necks. There was 1 mortality in a patient (6.3%) who experienced posterior cerebral artery and cerebellar strokes as well as subarachnoid hemorrhage after the placement of a flow diverter. Minor complications occurred in 2 patients (12.5%).\n\n\n\nFlow diversion for the treatment of basilar apex aneurysms results in acceptable occlusion rates in highly selected cases. Both primary flow diversion and rescue after failed clipping or coiling resulted in a modified Rankin Scale score that was either equal or better than at presentation and the technology represents a viable alternative or adjunctive option.",
"affiliations": "Division of Diagnostic and Therapeutic Neuroradiology, St. Michael's Hospital, Toronto, Ontario, Canada.;Division of Diagnostic and Therapeutic Neuroradiology, St. Michael's Hospital, Toronto, Ontario, Canada.;Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.;Division of Diagnostic and Therapeutic Neuroradiology, St. Michael's Hospital, Toronto, Ontario, Canada.;Division of Diagnostic and Therapeutic Neuroradiology, St. Michael's Hospital, Toronto, Ontario, Canada.;Division of Diagnostic and Therapeutic Neuroradiology, St. Michael's Hospital, Toronto, Ontario, Canada.;Department of Neurosurgery, University of Alabama at Birmingham, Alabama.;Department of Neurosurgery, State University of New York at Buffalo, Buffalo, New York.;Department of Interventional Neuroradiology, University of Florence, Florence, Italy.;Department of Interventional Neuroradiology, University of Florence, Florence, Italy.;Department of Diagnostic and Therapeutic Neuroradiology, Toulouse University Hospital, Toulouse, France.;Department of Medical Imaging, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.;Department of Medical Imaging, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.;Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut.;Department of Medical Imaging, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.;Department of Neurosurgery, University of Alabama at Birmingham, Alabama.;Department of Neurosurgery, State University of New York at Buffalo, Buffalo, New York.;Department of Neurosurgery, State University of New York at Buffalo, Buffalo, New York.;Department of Neurosurgery, State University of New York at Buffalo, Buffalo, New York.;Department of Interventional Neuroradiology, University of Florence, Florence, Italy.;Department of Diagnostic and Therapeutic Neuroradiology, Toulouse University Hospital, Toulouse, France.;Division of Diagnostic and Therapeutic Neuroradiology, St. Michael's Hospital, Toronto, Ontario, Canada.;Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.",
"authors": "Dmytriw|Adam A|AA|;Adeeb|Nimer|N|;Kumar|Ashish|A|;Griessenauer|Christoph J|CJ|;Phan|Kevin|K|;Ogilvy|Christopher S|CS|;Foreman|Paul M|PM|;Shallwani|Hussain|H|;Limbucci|Nicola|N|;Mangiafico|Salvatore|S|;Michelozzi|Caterina|C|;Krings|Timo|T|;Pereira|Vitor Mendes|VM|;Matouk|Charles C|CC|;Zhang|Yuchen|Y|;Harrigan|Mark R|MR|;Shakir|Hakeem J|HJ|;Siddiqui|Adnan H|AH|;Levy|Elad I|EI|;Renieri|Leonardo|L|;Cognard|Christophe|C|;Thomas|Ajith J|AJ|;Marotta|Thomas R|TR|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1093/neuros/nyx628",
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"issn_linking": "0148-396X",
"issue": "83(6)",
"journal": "Neurosurgery",
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"medline_ta": "Neurosurgery",
"mesh_terms": "D000328:Adult; D000368:Aged; D001807:Blood Vessel Prosthesis; D002140:California; D015331:Cohort Studies; D016208:Databases, Factual; D004621:Embolization, Therapeutic; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "7802914",
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"pages": "1298-1305",
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"pmid": "29529233",
"pubdate": "2018-12-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Flow Diversion for the Treatment of Basilar Apex Aneurysms.",
"title_normalized": "flow diversion for the treatment of basilar apex aneurysms"
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"dru... |
{
"abstract": "OBJECTIVE\nNeuroendocrine carcinoma of the cervix is a rare and aggressive subtype of cervical cancer and includes small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC). We conducted a single-institution retrospective review to explore the pattern of treatments and outcomes with the aim of defining an optimum treatment strategy for these carcinomas.\n\n\nMETHODS\nTwenty-three consecutive patients with SCNEC or LCNEC of the cervix diagnosed at the Hyogo Cancer Center between 1996 and 2013 were included in this study. Pertinent information, including clinical and pathological characteristics, and survival data were collected from clinical records and/or telephone surveys. The pathological review was conducted by a pathologist specializing in gynecologic cancer.\n\n\nRESULTS\nEleven patients had SCNEC and 12 had LCNEC. Eighteen patients with International Federation of Gynecology and Obstetrics (FIGO) stage I/II underwent type III radical hysterectomy with pelvic lymphadenectomy. After surgery, 9 received adjuvant chemotherapy (8, irinotecan plus cisplatin; 1, paclitaxel plus carboplatin), 7 received concurrent chemoradiation therapy (CCRT; 6, nedaplatin; 1, cisplatin), and 2 received radiation therapy (RT). Patients who received adjuvant chemotherapy had a better overall survival than did patients who received CCRT or RT (hazard ratio, 0.21; 95% confidence interval, 0.030-1.51; P = 0.12). Although the overall survival rates are not statistically significant, the 9 patients who underwent radical hysterectomy followed by adjuvant chemotherapy are all alive. Among the remaining 5 patients who did not undergo radical hysterectomy, 2 with FIGO stage III and 1 with stage IVa received CCRT, and 2 with stage IVb received palliative RT or chemotherapy. These 5 patients with FIGO stage III/IV died of disease within 36 months.\n\n\nCONCLUSIONS\nRadical hysterectomy followed by platinum-based chemotherapy, especially the irinotecan plus cisplatin combination, is beneficial for long-term survival in patients with early-stage neuroendocrine carcinoma of the cervix.",
"affiliations": "Departments of *Gynecologic Oncology and †Pathology, Hyogo Cancer Center, Akashi City, Hyogo, Japan.",
"authors": "Nagao|Shoji|S|;Miwa|Maiko|M|;Maeda|Naoko|N|;Kogiku|Ai|A|;Yamamoto|Kasumi|K|;Morimoto|Akemi|A|;Wakahashi|Senn|S|;Ichida|Kotaro|K|;Sudo|Tamotsu|T|;Yamaguchi|Satoshi|S|;Sakuma|Toshiko|T|;Fujiwara|Kiyoshi|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/IGC.0000000000000495",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1048-891X",
"issue": "25(7)",
"journal": "International journal of gynecological cancer : official journal of the International Gynecological Cancer Society",
"keywords": null,
"medline_ta": "Int J Gynecol Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D018287:Carcinoma, Large Cell; D018278:Carcinoma, Neuroendocrine; D018288:Carcinoma, Small Cell; D003131:Combined Modality Therapy; D019468:Disease Management; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "9111626",
"other_id": null,
"pages": "1300-5",
"pmc": null,
"pmid": "26166556",
"pubdate": "2015-09",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Clinical Features of Neuroendocrine Carcinoma of the Uterine Cervix: A Single-Institution Retrospective Review.",
"title_normalized": "clinical features of neuroendocrine carcinoma of the uterine cervix a single institution retrospective review"
} | [
{
"companynumb": "JP-CIPLA LTD.-2015JP07409",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
... |
{
"abstract": "For patients with acute myeloid leukemia (AML) relapsed after allogeneic bone marrow transplantation (BMT), donor leukocyte infusion (DLI) as sole therapy has very limited efficacy. We tested the effects of cytoreductive chemotherapy, followed immediately by G-CSF-primed DLI (chemotherapy followed by DLI, Chemo-DLI), in 16 AML patients who relapsed after allogeneic BMT. In all, 10 of these patients achieved complete remission (CR), four of whom remain alive in CR at a median follow-up of 1488 days after DLI. The 2-year overall survival (OS) for the entire cohort was 31%. The 1-year OS for patients with post-BMT remission of 6 months or longer was 55%, compared with 0% for patients with post-BMT remission of less than 6 months, making post-BMT remission duration the only significant prognostic factor for OS (P=0.015). These findings suggest that Chemo-DLI could induce durable remissions in a proportion of relapsed AML patients with relatively long post-BMT remission duration. All five patients who relapsed after achieving CR with Chemo-DLI relapsed at extramedullary sites in the presence of continuous bone marrow remission, suggesting uneven graft-versus-leukemia effects in different parts of the body. Although our data should be interpreted cautiously considering the limited number of patients, isolated extramedullary relapse seems to be common after Chemo-DLI.",
"affiliations": "Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. sjchoi3@amc.seoul.kr <sjchoi3@amc.seoul.kr>",
"authors": "Choi|S-J|SJ|;Lee|J-H|JH|;Lee|J-H|JH|;Kim|S|S|;Seol|M|M|;Lee|Y-S|YS|;Lee|J-S|JS|;Kim|W-K|WK|;Chi|H-S|HS|;Lee|K-H|KH|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor",
"country": "England",
"delete": false,
"doi": "10.1038/sj.leu.2403523",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "18(11)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D016026:Bone Marrow Transplantation; D006086:Graft vs Host Disease; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D015994:Incidence; D007951:Leukemia, Myeloid; D017708:Leukocyte Transfusion; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012074:Remission Induction; D015996:Survival Rate; D014019:Tissue Donors; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "1789-97",
"pmc": null,
"pmid": "15385924",
"pubdate": "2004-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Treatment of relapsed acute myeloid leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a high incidence of isolated extramedullary relapse.",
"title_normalized": "treatment of relapsed acute myeloid leukemia after allogeneic bone marrow transplantation with chemotherapy followed by g csf primed donor leukocyte infusion a high incidence of isolated extramedullary relapse"
} | [
{
"companynumb": "KR-BAXTER-2018BAX012482",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Although hematopoietic stem cell transplantation (HSCT) may increase the curability of refractory hematologic diseases, it requires complication management due to a long-term immunocompromised state. We experienced a case who received an autologous peripheral blood stem cell transplantation (Auto-PBSCT) for POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) and developed cutaneous Mycobacterium chelonae infection. It is clear that attention needs to be paid to prevent bacterial, fungal and viral infection after HSCT. It is also important to keep in mind that tuberculous and nontuberculous mycobacteria (NTM), in rare cases, lead to lethal complications.",
"affiliations": "Department of Hematology, Tottori Prefectural Central Hospital, Tottori, Japan. Electronic address: 98069yh@jichi.ac.jp.;Department of Dermatology, Tottori Prefectural Central Hospital, Tottori, Japan.;Department of Pathology, Tottori Prefectural Central Hospital, Tottori, Japan.;Department of Hematology, Tottori Prefectural Central Hospital, Tottori, Japan.;Department of Hematology, Tottori Prefectural Central Hospital, Tottori, Japan.",
"authors": "Hashimoto|Yoshinori|Y|;Ikeda|Ayano|A|;Tokuyasu|Yusuke|Y|;Omura|Hiromi|H|;Tanaka|Takayuki|T|",
"chemical_list": "D004269:DNA, Bacterial",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2018.05.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "24(12)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Autologous; Hematopoietic stem cell transplantation; Mycobacterium chelonae; Nontuberculous mycobacteria",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000368:Aged; D004269:DNA, Bacterial; D005260:Female; D005684:Gait; D006099:Granuloma; D006801:Humans; D006987:Hypesthesia; D009165:Mycobacterium Infections, Nontuberculous; D016926:Mycobacterium chelonae; D016878:POEMS Syndrome; D036102:Peripheral Blood Stem Cell Transplantation; D012867:Skin; D014182:Transplantation, Autologous",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "983-986",
"pmc": null,
"pmid": "29861185",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cutaneous Mycobacterium chelonae infection following autologous peripheral blood stem cell transplantation for POEMS syndrome.",
"title_normalized": "cutaneous mycobacterium chelonae infection following autologous peripheral blood stem cell transplantation for poems syndrome"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1089050",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
},
"drugadditional": "1",
... |
{
"abstract": "This case report describes a patient, who presented with extrapyramidal side effects to the treatment with metoclopramide, which is used as an antiemetic, for gastroparesis and reflux. However, beyond its desired effect, serious neurological adverse reactions can be seen, which is why the European Medicines Agency and the Danish Medicines Agency have changed the recommendations for its use. If the extrapyramidal side effects include the respiratory muscles, the patient's ability to breathe can be affected. If a patient receiving metoclopramide or anti-psychotic drugs shows signs of tachypnoea or acute respiratory distress, the possibility of respiratory dyskinesia should always be considered.",
"affiliations": "peter.lange@sund.ku.dk.",
"authors": "Vorre|Mette Medom|MM|;Lange|Peter|P|",
"chemical_list": "D000932:Antiemetics; D008787:Metoclopramide",
"country": "Denmark",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-5782",
"issue": "181(17)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D000932:Antiemetics; D004409:Dyskinesia, Drug-Induced; D018589:Gastroparesis; D006801:Humans; D008787:Metoclopramide",
"nlm_unique_id": "0141730",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31036138",
"pubdate": "2019-04-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metoclopramide-induced respiratory dyskinesia.",
"title_normalized": "metoclopramide induced respiratory dyskinesia"
} | [
{
"companynumb": "DK-TEVA-2020-DK-1793132",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METOCLOPRAMIDE"
},
"drugadditional": "1",
... |
{
"abstract": "Immunosuppressive therapy is today's standard treatment of patients with moderate to severe inflammatory bowel disease (IBD). The risk for opportunistic infections is increased due to this therapy and is a concern in the management of patient with IBD undergoing such a treatment.\n\n\n\nIn this paper, we describe a case of an acute cytomegalovirus (CMV) infection in a 35-year-old male patient with Crohn's disease being in remission while receiving azathioprine therapy. His clinical presentation was high-grade fever, night sweats, skin rash, and abdominal pain.Laboratory findings showed pancytopenia, elevated liver enzymes, and high ferritin levels. Sonographic examination revealed splenomegaly and serological analysis proved an acute CMV infection. The severity of the acute illness and these results in the setting of immunosuppressive treatment with azathioprine were highly suspicious of hemophagocytic lymphohistiocytosis (HLH).Further investigations including bone marrow biopsy, analysis of natural killer cell function, and measurement of T-cell activity confirmed the suspected diagnosis. Treatment consisted of antiviral and symptomatic therapy.\n\n\n\nHLH is a rare and severe condition triggered by uncontrolled stimulation of histiocytes and lymphocytes, resulting in abnormal cytokine production. The causes can be primary (genetic) or secondary due to acquired immunodeficiency or viral infections such as CMV. Several symptoms of this condition are unspecific, but the summary of clinical symptoms and signs are diagnostic. Treatment consists of specific intervention if possible and application of immunosuppressive drugs such as corticosteroids.",
"affiliations": "Fifth Department of Medicine, Klinikum Wels-Grieskirchen, Austria.;Fifth Department of Medicine, Klinikum Wels-Grieskirchen, Austria.;Institute of Laboratory Medicine, Klinikum Wels-Grieskirchen, Austria.;Institute of Pathology, Klinikum Wels-Grieskirchen, Austria.;Institute of Microbiology, Klinikum Wels-Grieskirchen, Austria.;Institute of Microbiology, Klinikum Wels-Grieskirchen, Austria.;Fifth Department of Medicine, Klinikum Wels-Grieskirchen, Austria.",
"authors": "Miechowiecki|Jan|J|;Stainer|Waltraud|W|;Wallner|Gertraud|G|;Tuppy|Herwig|H|;Aichinger|Walter|W|;Prammer|Wolfgang|W|;Kirchgatterer|Andreas|A|",
"chemical_list": "D000998:Antiviral Agents; D001379:Azathioprine",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0043-123999",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0044-2771",
"issue": "56(3)",
"journal": "Zeitschrift fur Gastroenterologie",
"keywords": null,
"medline_ta": "Z Gastroenterol",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D001379:Azathioprine; D003424:Crohn Disease; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D006801:Humans; D007249:Inflammation; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D016896:Treatment Outcome",
"nlm_unique_id": "0033370",
"other_id": null,
"pages": "259-263",
"pmc": null,
"pmid": "29529681",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe complication during remission of Crohn's disease: hemophagocytic lymphohistiocytosis due to acute cytomegalovirus infection.",
"title_normalized": "severe complication during remission of crohn s disease hemophagocytic lymphohistiocytosis due to acute cytomegalovirus infection"
} | [
{
"companynumb": "AT-MYLANLABS-2017M1067390",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "1",
... |
{
"abstract": "Intrathecal administration of digoxin occurs very rarely. Some case reports of inadvertently administering it when performing spinal/epidural anesthesia were described. We report for the first time a case of a chemical meningitis and status epilepticus caused by accidental epidural administration of digoxin. A 26-year-old female underwent epidural anesthesia for a planned cesarean section (CS). Post operatively the patient became lethargic, agitated and encephalopathic, she was intubated and transferred to our hospital intensive care unit (ICU). She had seizures on admission. Electroencephalogram (EEG) was performed and showed generalized slowing and status epilepticus with a focus noted in the right temporal region which resolved after antiepileptic medication administration. A lumbar puncture (LP) was performed; cerebro-spinal fluid (CSF) was suggestive for meningitis. However, there was no evidence for viral or bacterial infections. Within a day of admission, the referring hospital informed us that the patient received 250 mcg of digoxininadvertently-through epidural injection. The patient remained intubated for four days. She became more responsive and alert and was eventually extubated. After extubation, the patient was responsive and full neurological exam and brain imaging were normal. She was discharged from the hospital after seven days.",
"affiliations": "University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota.;University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota.;University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota.;Avera McKennan Hospital and University Health Center, Sioux Falls, South Dakota.",
"authors": "Abdallah|Mohamed A|MA|;Xie|Chencheng|C|;Ahmed|Khalid Mohamed|KM|;Hericks|Anthony J|AJ|",
"chemical_list": "D004077:Digoxin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0038-3317",
"issue": "72(7)",
"journal": "South Dakota medicine : the journal of the South Dakota State Medical Association",
"keywords": null,
"medline_ta": "S D Med",
"mesh_terms": "D000328:Adult; D000767:Anesthesia, Epidural; D002585:Cesarean Section; D004077:Digoxin; D005260:Female; D006801:Humans; D008581:Meningitis; D011247:Pregnancy; D013226:Status Epilepticus",
"nlm_unique_id": "101265265",
"other_id": null,
"pages": "310-312",
"pmc": null,
"pmid": "31461586",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Chemical Meningitis and Status Epilepticus Caused by Accidental Epidural Administration of Digoxin.",
"title_normalized": "chemical meningitis and status epilepticus caused by accidental epidural administration of digoxin"
} | [
{
"companynumb": "US-MYLANLABS-2019M1091538",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nOvarian cancer is usually diagnosed at an advanced stage, with most patients undergoing surgery followed by platinum- and taxane-based chemotherapy. After initial clinical remission, the majority recur, leading to additional treatments, including not only platinums and taxanes but also pegylated liposomal doxorubicin (PLD), gemcitabine, topotecan, and, more recently, bevacizumab, which may extend survival times. PLD, in particular, has been extensively studied by our group, with encouraging therapeutic results. We, however, observed instances of chronic kidney disease (CKD) developing among patients who received long-term treatment for recurrent ovarian cancer. To document the frequency and contributing factors to the emergence of CKD, we initiated a retrospective review at two institutions.\n\n\nMETHODS\nFifty-six consecutive patients with recurrent ovarian cancer receiving treatment at New York University Cancer Institute were reviewed for the presence of renal disease in 1997-2010. At Shaare Zedek Medical Center, 73 consecutive patients with ovarian cancer were reviewed in 2002-2010. Patients were diagnosed with CKD if they had an estimated GFR <60 mL/minute per 1.73 m2 for >3 months and were staged according to the National Kidney Foundation guidelines.\n\n\nRESULTS\nThirteen patients (23%) developed stage ≥3 CKD. Three patients had renal biopsies performed that showed thrombotic microangiopathy.\n\n\nCONCLUSIONS\nCKD is emerging as a potential long-term consequence of current chemotherapy for recurrent ovarian cancer.",
"affiliations": "NYU Clinical Cancer Center, 550 First Avenue, New York, NY 10016, USA.",
"authors": "Kwa|Maryann|M|;Baumgartner|Robert|R|;Shavit|Linda|L|;Barash|Irina|I|;Michael|Jeffrey|J|;Puzanov|Igor|I|;Kopolovic|Juri|J|;Rosengarten|Ora|O|;Blank|Stephanie|S|;Curtin|John P|JP|;Gabizon|Alberto|A|;Muggia|Franco|F|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D043823:Taxoids; C506643:liposomal doxorubicin; D003841:Deoxycytidine; D000068258:Bevacizumab; D011092:Polyethylene Glycols; D010984:Platinum; D019772:Topotecan; D004317:Doxorubicin; D003404:Creatinine; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2011-0422",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "17(12)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D003404:Creatinine; D003841:Deoxycytidine; D004317:Doxorubicin; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms; D010984:Platinum; D011092:Polyethylene Glycols; D011788:Quality of Life; D012008:Recurrence; D051436:Renal Insufficiency, Chronic; D012189:Retrospective Studies; D012307:Risk Factors; D043823:Taxoids; D013927:Thrombosis; D019772:Topotecan",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "1534-40",
"pmc": null,
"pmid": "22622146",
"pubdate": "2012",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016448:Multicenter Study",
"references": "21175974;11038041;16908915;22529265;6172662;11904577;17301073;12739982;11012915;16870316;10223245;18337603;3461207;15717738;12748199;18977023;9060537;7602367;18272962;15590954;2182639;21115880",
"title": "Is renal thrombotic angiopathy an emerging problem in the treatment of ovarian cancer recurrences?",
"title_normalized": "is renal thrombotic angiopathy an emerging problem in the treatment of ovarian cancer recurrences"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-338301",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"dr... |
{
"abstract": "We present a possible important association of tumor necrosis factor-alpha inhibition (TNFa-i) and erectile function in a male patient with rheumatoid arthritis (RA). Long-standing, untreated RA may result in significant physical limitation and disability, however often overlooked is the association between RA and erectile and sexual dysfunction. Ischemic priapism is currently unrecognized as an adverse reaction associated with TNFa-i use and there have been no reported cases with adalimumab. Our patient, a 58-year-old Hispanic man, with sero-positive, erosive RA developed persistent priapism (17 days) despite multiple urologic interventions after initial adalimumab 40 mg administration. TNFa has recently been implicated as a potential factor in erectile dysfunction through its role in vascular reactivity. Excess TNFa, from active RA, may perturb intracavernosal smooth muscle and endothelial cell function; theoretically, TNFa inhibition may then causes excess local nitric oxide production and subsequent priapism. The potential role of TNFa-i in ED and risk for priapism is an important area for future study.",
"affiliations": "Division of Rheumatology, Department of Medicine, Keck School of Medicine at University of Southern California, Hoffman Medical Research Center, 2011 Zonal Ave, HMR 711, Los Angeles, CA, 90033, USA, ajk_001@usc.edu.",
"authors": "Kreitenberg|Adam J|AJ|;Ortiz|Elizabeth C|EC|;Arkfeld|Daniel G|DG|",
"chemical_list": "D018501:Antirheumatic Agents; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000068879:Adalimumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-014-2858-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "34(4)",
"journal": "Clinical rheumatology",
"keywords": null,
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000068879:Adalimumab; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D006630:Hispanic or Latino; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide; D010413:Penis; D011317:Priapism; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "801-2",
"pmc": null,
"pmid": "25579651",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22219142;24314827;19759542;20345734;24363861;17056702",
"title": "Priapism after tumor necrosis factor alpha inhibitor use.",
"title_normalized": "priapism after tumor necrosis factor alpha inhibitor use"
} | [
{
"companynumb": "US-ABBVIE-15P-163-1338240-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of pulmonary embolism in a patient who presented with repeated anxiety attacks and psychotic symptoms and was misdiagnosed as having withdrawal seizure or anxiety disorder not otherwise specified. This case highlighted the nonspecific clinical features of pulmonary embolism and the principles in making psychiatric diagnosis. Careful history taking, thorough physical examination, appropriate investigation, and a high index of suspicion led to the correct diagnosis. The principle of hierarchy of psychiatric diagnosis (ie, organic over non-organic) and the possibility of comorbidities should always apply.",
"affiliations": "Department of Psychiatry, Prince of Wales Hospital / Shatin Hospital.;Department of Psychiatry, University of Hong Kong.;Chinese University of Hong Kong.",
"authors": "Wong|M F K|MFK|;Leung|M W M|MWM|;Leung|C M|CM|",
"chemical_list": null,
"country": "China",
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"issue": "29(3)",
"journal": "East Asian archives of psychiatry : official journal of the Hong Kong College of Psychiatrists = Dong Ya jing shen ke xue zhi : Xianggang jing shen ke yi xue yuan qi kan",
"keywords": null,
"medline_ta": "East Asian Arch Psychiatry",
"mesh_terms": "D001007:Anxiety; D001008:Anxiety Disorders; D003951:Diagnostic Errors; D004417:Dyspnea; D006801:Humans; D008297:Male; D008875:Middle Aged; D011655:Pulmonary Embolism; D012640:Seizures; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "101536416",
"other_id": null,
"pages": "97-98",
"pmc": null,
"pmid": "31566187",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "'Organic Anxiety' in a Middle-aged Man Presenting with Dyspnoea: a Case Report.",
"title_normalized": "organic anxiety in a middle aged man presenting with dyspnoea a case report"
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"abstract": "We present 2 fatal cases of invasive fungal disease with isavuconazole treatment failure in immunocompromised patients: one with a TR34-L98H azole-resistant Aspergillus fumigatus isolate and the other a Rhizomucor-A. fumigatus co-infection. Such patients probably require surveillance by galactomannan antigen detection and quantitative PCRs for A. fumigatus and Mucorales fungi.",
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"authors": "Bellanger|Anne-Pauline|AP|;Berceanu|Ana|A|;Scherer|Emeline|E|;Desbrosses|Yohan|Y|;Daguindau|Etienne|E|;Rocchi|Steffi|S|;Millon|Laurence|L|",
"chemical_list": "D000935:Antifungal Agents; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole",
"country": "United States",
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"doi": "10.3201/eid2509.190598",
"fulltext": "\n==== Front\nEmerg Infect Dis\nEmerging Infect. Dis\nEID\nEmerging Infectious Diseases\n1080-6040\n1080-6059\nCenters for Disease Control and Prevention\n\n31441760\n19-0598\n10.3201/eid2509.190598\nResearch Letter\nResearch Letter\nInvasive Fungal Disease, Isavuconazole Treatment Failure, and Death in Acute Myeloid Leukemia Patients\nInvasive Fungal Disease, Isavuconazole Treatment Failure, and Death in Acute Myeloid Leukemia Patients\nInvasive Fungal Disease, Isavuconazole Treatment Failure, Death in Acute Myeloid Leukemia Patients\nBellanger Anne-Pauline\nBerceanu Ana\nScherer Emeline\nDesbrosses Yohan\nDaguindau Etienne\nRocchi Steffi\nMillon Laurence\nUniversity Hospital, Besançon, France (A.-P. Bellanger, E. Scherer, S. Rocchi, L. Millon);\nFranche-Comté University, Besançon (A.-P. Bellanger, E. Scherer, L. Millon);\nBesançon University Hospital, Besançon (A. Berceanu, Y. Desbrosses, E. Daguindau)\nAddress for correspondence: Anne-Pauline Bellanger, Department of Parasitology-Mycology, Besançon University Hospital Jean Minjoz, 2 Blvd Fleming, 25030 Besançon CEDEX, France; email: apbellanger@chu-besancon.fr\n9 2019\n25 9 17781779\nWe present 2 fatal cases of invasive fungal disease with isavuconazole treatment failure in immunocompromised patients: one with a TR34-L98H azole–resistant Aspergillus fumigatus isolate and the other a Rhizomucor–A. fumigatus co-infection. Such patients probably require surveillance by galactomannan antigen detection and quantitative PCRs for A. fumigatus and Mucorales fungi.\n\nKeywords:\n\naspergillosis\nfungal co-infection\ninvasive fungal disease\nisavuconazole\ntreatment failure\nmucormycosis\nquantitative PCR\nqPCR\ncomputed tomography\nCT\ngraft-versus-host disease\nAspergillus fumigatus\nRhizomucor\nFrance\nantimicrobial resistance\nfungi\nacute myeloid leukemia\nhematopoietic stem-cell transplantation\ngalactomannan antigen\nimmunocompromised patients\ndeath\n==== Body\nIsavuconazole, an antifungal azole used to treat invasive fungal diseases (IFDs), is approved as a first-line treatment for invasive aspergillosis and can be used as an alternative treatment for mucormycosis (1). We present 2 cases of IFD and isavuconazole treatment failure in acute myeloid leukemia (AML) patients with prolonged neutropenia after hematopoietic stem-cell transplantation (SCT).\n\nPatient 1, a 52-year-old truck driver with AML (diagnosed in 2017), received a haplo-identical SCT (day 0) 4 months after the diagnosis. The patient had incomplete hematologic reconstitution and experienced graft-versus-host disease of the digestive tract (day 0), which we treated with corticosteroids and ruxolitinib. We gave the patient oral posaconazole (300 mg/day, starting day 1) for IFD prophylaxis, as recommended by the 4th European Conference on Infections in Leukaemia (2). On about day 65, we diagnosed probable invasive aspergillosis according to the criteria of the European Organisation for Research and Treatment of Cancer Mycoses Study Group (3,4); the patient had fever, neutropenia, and a discrete pulmonary lesion on chest computed tomography (CT), and serum samples were repeatedly positive by an in-house A. fumigatus quantitative PCR (qPCR) but negative for galactomannan antigen (Figure) (1,4). On the same day, we switched treatment to oral isavuconazole (200 mg/day). On day 126, chest CT showed the persistence of pulmonary lesions, and we switched patient treatment to liposomal amphotericin B (5 mg/day by injection). Thereafter, serum samples became repeatedly positive for galactomannan antigen and A. fumigatus DNA. At day 158, we found TR34-L98H azole–resistant A. fumigatus fungus in his bronchial aspirate. The French National Reference Center for Invasive Mycoses and Antifungals (Paris, France) performed MIC testing using European Committee on Antibiotic Susceptibility Testing methods (https://www.pasteur.fr/fr/sante-publique/CNR/les-cnr/mycoses-invasives-antifongiques). The following MICs were obtained: amphotericin B 0.25 mg/L (susceptibility unknown, no breakpoint available), itraconazole >8 mg/L (resistant), isavuconazole 4 mg/L (resistant), and voriconazole 2 mg/L (susceptible). The patient died 182 days after the SCT.\n\nFigure Evolution of fungal biomarkers, computed tomography chest scans, and antifungal treatments for immunocompromised patient 1 with invasive Aspergillus fumigatus infection, France, 2018. Arrows indicate lesions. qPCR, quantitative PCR.\n\nPatient 2, a 61-year-old businessman with AML (diagnosed in 2013), received his first allogenic hematopoietic SCT 4 months after the diagnosis. He experienced a relapse 3 years after the first transplantation, and a second allogenic hematopoietic SCT was performed (day 0), which was followed by severe sepsis with Escherichia coli. An excavated nodule was visible on chest CT (day 4), and the A. fumigatus biomarker was repeatedly positive, suggesting probable invasive aspergillosis according to European Organisation for Research and Treatment of Cancer criteria (3). On day 5, treatment with isavuconazole (200 mg/day orally) was initiated. Graft-versus-host disease of the digestive tract also developed (day 12) in this patient, which we treated with ruxolitinib, tacrolimus, and prednisolone. On day 92, the patient had asthenia, fever, and thoracic pain, and chest CT showed multiple micronodules. On days 95–116, systematic fungal surveillance testing of serum samples showed 1 test positive for galactomannan antigen, 4 positive for A. fumigatus DNA, and 3 positive for Rhizomucor DNA. Two cultured pulmonary samples collected on days 114 and 116 were positive for A. fumigatus. We performed ETESTs (bioMérieux, https://www.biomerieux-diagnostics.com), which indicated the following MICs: amphotericin B 0.023 mg/L (susceptibility unknown), isavuconazole 0.25 mg/L (susceptible), and voriconazole 0.38 mg/L (susceptible). We switched patient treatment to liposomal amphotericin B (5 mg/kg by injection) on day 117, but the patient died on day 129.\n\nThese 2 cases had in common AML treated by SCT, followed by severe digestive graft-versus-host disease, IFD resistant to isavuconazole diagnosed >100 days after SCT, use of combined fungal biomarkers to detect IFD, and death despite rapid prescription of amphotericin B. Severe digestive graft-versus-host disease might have affected the levels of isavuconazole absorbed by the patient because the drug was administered orally in both cases. Intravenous isavuconazole is not recommended for treating IFD and was not available at the treatment facility (University Hospital, Besançon, France). However, these cases suggest that isavuconazole levels should be checked in patients with severe digestive graft-versus-host disease. For patient 1, a change in class of antifungal drugs could have been made as early as day 65, and earlier treatment with amphotericin B could have had a positive effect on his prognosis. The long duration between the initial positive qPCR and galactomannan antigen test result suggests patient 1 might have been infected with multiple A. fumigatus isolates, with 1 being resistant. For patient 2, the systematic use of Mucorales qPCR enabled early detection of a mixed Aspergillus-Mucorales fungal infection (5). These types of mixed mold infection were reported to have a prevalence of 25% in studies including Mucorales qPCR (6). The diagnosis of Rhizomucor infection was based on 3 successive samples being positive by Rhizomucor qPCR. A Mucorales qPCR of the patient’s bronchoalveolar lavage fluid (validated assay with satisfying sensitivity) was surprisingly negative (6).\n\nIn summary, these cases demonstrate that systematic surveillance is needed for severely immunocompromised patients treated for IFD. Galactomannan antigen detection and qPCRs targeting Aspergillus fumigatus and Mucorales fungi might be the optimal surveillance strategy.\n\nAcknowledgments\n\nWe thank Pamela Albert for her editorial assistance.\n\nDr. Bellanger is a microbiologist involved in the diagnosis of invasive fungal infections at University Hospital, Besançon, France. Her research focus is on invasive aspergillosis and mucormycosis.\n\nSuggested citation for this article: Bellanger AP, Berceanu A, Scherer E, Desbrosses Y, Daguindau E, Rocchi S, et al. Invasive fungal disease, isavuconazole treatment failure, and death in acute myeloid leukemia patients. Emerg Infect Dis. 2019 Sep [date cited]. https://doi.org/10.3201/eid2509.190598\n==== Refs\nReferences\n\n1. Cresemba® (isavuconazium sulfate) [package insert]. Northbrook (IL): Astellas Pharma US, Inc.;2015.\n2. Groll AH, Castagnola E, Cesaro S, Dalle JH, Engelhard D, Hope W, et al. ; Fourth European Conference on Infections in Leukaemia; Infectious Diseases Working Party of the European Group for Blood Marrow Transplantation (EBMT-IDWP); Infectious Diseases Group of the European Organisation for Research and Treatment of Cancer (EORTC-IDG); International Immunocompromised Host Society (ICHS); European Leukaemia Net (ELN). Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation. Lancet Oncol. 2014;15 :e327–40. 10.1016/S1470-2045(14)70017-8 24988936\n3. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. ; European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46 :1813–21. 10.1086/588660 18462102\n4. Ullmann AJ, Aguado JM, Arikan-Akdagli S, Denning DW, Groll AH, Lagrou K, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018;24 (Suppl 1 ):e1–38. 10.1016/j.cmi.2018.01.002 29544767\n5. Millon L, Scherer E, Rocchi S, Bellanger AP. Molecular strategies to diagnose mucormycosis. J Fungi (Basel). 2019;5 :24. 10.3390/jof5010024 30897709\n6. Scherer E, Iriart X, Bellanger AP, Dupont D, Guitard J, Gabriel F, et al. Quantitative PCR (qPCR) detection of Mucorales DNA in bronchoalveolar lavage fluid to diagnose pulmonary mucormycosis. J Clin Microbiol. 2018;56 :e00289–18. 10.1128/JCM.00289-18 29875192\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1080-6040",
"issue": "25(9)",
"journal": "Emerging infectious diseases",
"keywords": "Aspergillus fumigatus; CT; France; Rhizomucor; acute myeloid leukemia; antimicrobial resistance; aspergillosis; computed tomography; death; fungal co-infection; fungi; galactomannan antigen; graft-versus-host disease; hematopoietic stem-cell transplantation; immunocompromised patients; invasive fungal disease; isavuconazole; mucormycosis; qPCR; quantitative PCR; treatment failure",
"medline_ta": "Emerg Infect Dis",
"mesh_terms": "D000935:Antifungal Agents; D001232:Aspergillus fumigatus; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D006801:Humans; D016867:Immunocompromised Host; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D055732:Pulmonary Aspergillosis; D011725:Pyridines; D017211:Treatment Failure; D014230:Triazoles",
"nlm_unique_id": "9508155",
"other_id": null,
"pages": "1778-1779",
"pmc": null,
"pmid": "31441760",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": "29544767;29875192;24988936;18462102;30897709",
"title": "Invasive Fungal Disease, Isavuconazole Treatment Failure, and Death in Acute Myeloid Leukemia Patients.",
"title_normalized": "invasive fungal disease isavuconazole treatment failure and death in acute myeloid leukemia patients"
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{
"abstract": "BACKGROUND\nHoffmann's syndrome is a rare form of hypothyroid myopathy. Only a few cases of fasciotomy in this setting have previously been reported.\n\n\nMETHODS\nA 41-year-old Caucasian man under treatment for hypothyroidism presented with acute-onset severe pain in his forearm for no obvious reason and was admitted to our emergency room. He eventually developed compartment syndrome which necessitated surgical decompression. Soon after surgery he complained of similar symptoms in his calves. By the time his hypothyroid status was confirmed, conservative treatment and orally administered levothyroxine gradually made the pain from his calves disappear, without further surgical treatment.\n\n\nCONCLUSIONS\nHoffmann's syndrome may precipitate a compartment syndrome in the absence of trauma.",
"affiliations": "Department of Urology and Endocrine Surgery, University Hospital of North Norway, Tromsø, Norway. erling.johan.aarsaether@unn.no.;Department of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway.;Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway.;Department of Radiology, University Hospital of North Norway, Tromsø, Norway.;Department of Anesthesia, University Hospital of North Norway, Tromsø, Norway.;Department of Urology and Endocrine Surgery, University Hospital of North Norway, Tromsø, Norway.",
"authors": "Aarsæther|Erling|E|;Joakimsen|Ragnar|R|;Halvorsen|Hanne|H|;Sildnes|Trude|T|;Sivertsen|Olav|O|;Due|Jan|J|",
"chemical_list": "D013974:Thyroxine",
"country": "England",
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"doi": "10.1186/s13256-020-2351-x",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n2351\n10.1186/s13256-020-2351-x\nCase Report\nHoffmann’s syndrome necessitating forearm fasciotomy: a case report\nAarsæther Erling erling.johan.aarsaether@unn.no 12 Joakimsen Ragnar ragnar.joakimsen@unn.no 23 Halvorsen Hanne hanne.halvorsen@unn.no 4 Sildnes Trude trude.sildnes@unn.no 5 Sivertsen Olav olav.m.sivertsen@unn.no 6 Due Jan jan.due@unn.no 1 1 grid.412244.50000 0004 4689 5540Department of Urology and Endocrine Surgery, University Hospital of North Norway, Tromsø, Norway \n2 grid.10919.300000000122595234Department of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway \n3 grid.412244.50000 0004 4689 5540Department of Endocrinology, University Hospital of North Norway, Tromsø, Norway \n4 grid.412244.50000 0004 4689 5540Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway \n5 grid.412244.50000 0004 4689 5540Department of Radiology, University Hospital of North Norway, Tromsø, Norway \n6 grid.412244.50000 0004 4689 5540Department of Anesthesia, University Hospital of North Norway, Tromsø, Norway \n2 3 2020 \n2 3 2020 \n2020 \n14 382 7 2019 20 1 2020 © The Author(s). 2020Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nHoffmann’s syndrome is a rare form of hypothyroid myopathy. Only a few cases of fasciotomy in this setting have previously been reported.\n\nCase presentation\nA 41-year-old Caucasian man under treatment for hypothyroidism presented with acute-onset severe pain in his forearm for no obvious reason and was admitted to our emergency room. He eventually developed compartment syndrome which necessitated surgical decompression. Soon after surgery he complained of similar symptoms in his calves. By the time his hypothyroid status was confirmed, conservative treatment and orally administered levothyroxine gradually made the pain from his calves disappear, without further surgical treatment.\n\nConclusion\nHoffmann’s syndrome may precipitate a compartment syndrome in the absence of trauma.\n\nKeywords\nCompartment syndromeFasciotomyHoffmann’s syndromeHypothyroidismissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nAn acute compartment syndrome of the forearm usually occurs as a result of trauma or ischemia. The non-compliant fascia surrounding the muscles essentially creates a closed compartment, which is vulnerable to all processes that expand muscle volume and therefore the intra-compartment pressure. Any pressure increase beyond a certain threshold is likely to compromise micro-circulation, and may elicit the self-perpetuating process that increases the intra-compartment pressure at the expense of circulation. The result is muscular ischemia, which produces the cardinal symptom of acute compartment syndrome; that is, excessive pain. An acute compartment syndrome represents an emergency situation, in which failure to surgically open the fascia in due time, may lead to muscle necrosis or even amputation. We present a case in which a patient developed a compartment syndrome of his forearm for no obvious reason. To the best of our knowledge, this is the first report of a patient with Hoffmann’s syndrome presenting with a compartment syndrome of the forearm described in the medical literature.\n\nCase presentation\nA 41-year-old Caucasian man presented to hospital with intense pain in his right forearm. The pain exhibited a gradual onset over 2 days, but was abruptly worsened following the simple task of tightening a screw with a screwdriver. His background was from a middle class family with no known risk of hereditary disease. He was in a stable relationship and the father of two children, both in their twenties, from a previous marriage. After completing high school he had earned a university degree in education of children with disabilities, which was also his current profession. His alcohol consumption was moderate and he did not smoke tobacco. Despite his relatively young age, his medical record contained a comprehensive list of previous diseases. At age 25 he underwent fundoplication because of gastric reflux. The procedure was repeated 3 years later due to persisting symptoms. At 29 he was diagnosed as having Hodgkin’s lymphoma. He initially received combination chemotherapy of doxorubicin, bleomycin, vinblastine, and dacarbazine, but this was terminated due to development of leg weakness. To compensate for chemotherapy intolerance, he subsequently received radiotherapy toward lymph nodes in his neck with a total of 40 gray. Consequently, he developed hypothyroidism as a side effect.\n\nHe had previously been on thyroid hormone replacement therapy for 7 years. During these years he had been changing the thyroxine medication from synthetic levothyroxine to a preparation derived from porcine thyroid glands, before ending up with a combination of the two. The previous 6 months he had expressed frustration over a general lack of well-being, claiming that the current thyroid hormone replacement therapy did not improve his symptoms. During several visits to his endocrinologist he had communicated a strong desire to discontinue thyroxine hormone replacement therapy completely, in order to see whether it would make him feel better. The idea was supported by his endocrinologist, provided that he, the patient, would be willing to control thyroid function every week, in collaboration with his general physician. In the months leading up to the decision to abandon levothyroxine therapy completely, our patient’s medical record indicated that he was on a natural preparation derived from porcine thyroid glands corresponding to a daily dose of 19 μg of levothyroxine and 4.5 μg of liothyronine in addition to 50 μg of levothyroxine 4 days a week and 25 μg of levothyroxine the remaining 3 days. Approximately 3 months after he had in fact discontinued thyroxine hormone replacement therapy completely, he found himself being examined in the emergency unit because of acute severe pain in his right forearm. At the time of admission, his regular medication included esomeprazole 40 mg twice a day and 100 mg of ferrous sulfate once a day only.\n\nDuring clinical examination in the emergency unit after midnight, severe pain was located on the dorsal side of his right forearm. His arm appeared swollen on examination, but the overlying skin was completely normal. A brief neurological examination revealed reduced sensibility to sensation on his right forearm compared to his left, especially on the ulnar side. Brachioradial reflexes were normal on both sides, whereas biceps and triceps reflexes were unsuccessfully elicited on either side. Reduced muscular power was described in his fingers and wrist on the right side, but our patient spontaneously disclosed that this was due to the pain being increased during contraction of these muscles. His blood pressure was 165/102 mmHg, pulse 90 beats/minute, respiratory rate 22 per/minute, and rectal temperature 37.0 °C. He did not present any obvious symptoms or clinical signs frequently seen in hypothyroidism, such as lethargy, hair loss, cold intolerance, or myxedema. His creatinine kinase was elevated to 1659 IU/L (range 40–280). The results of a screening of blood tests including complete blood count, liver function tests, renal function tests, and C-reactive protein were all within the reference range. The resident surgeon ordered overnight elevation of our patient’s arm and opioid analgesics. Despite repeated administration of orally administered analgesics (1 g acetaminophen every 6 hours, 50 mg tramadol hydrochloride once) and intravenously administered opioid analgesics (5 mg oxycodone every 2 hours for 8 hours, followed by 5 mg morphine every 2 hours for 8 hours), he continued to complain of intense pain in his right forearm. The next morning a clinical evaluation of our patient revealed no improvement in pain or edema. His creatinine kinase had increased slightly to 1722 IU/L, and the surgeon on call diagnosed our patient as having compartment syndrome and referred him for immediate surgery. A preoperative computed tomography (CT) scan was performed, which revealed edema in the extensor carpi ulnaris muscle (Fig. 1), but no signs of an underlying process such as bleeding, tumor, or abscess. Complementary blood tests revealed a thyroid-stimulating hormone of 30.5 μIU/ml (range 0.2–4.3) and free thyroxine of 7 μmol/L (range 9–22), indicating hypothyroidism. A summary of the blood samples and their timing is provided in Table 1. After induction of general anesthesia by a combination of remifentanil (1 μg/kg per minute), propofol (180 mg), succinylcholine (80 mg) and fentanyl (200 μg), a straightforward fasciotomy was performed. The diagnosis of compartment syndrome was subsequently confirmed by the bulging of the affected muscle following opening of the fascia.\nFig. 1 Preoperative computed tomography scan with arrows pointing at dark areas in the right extensor carpi ulnaris muscle, indicating edema. a Coronal plane; b transverse plane, middle; c transverse plane, proximal\n\nTable 1 Relevant blood samples and their timing\n\nTiming of blood samples\tTSH (μIU/ml)\tfT4 (μmol/L)\tCK (IU/L)\t\nReference range\t(0.20–4.30)\t(9–22)\t(40–280)\t\nFour weeks before admission in EU\t11.8\t7\tnm\t\nEight hours before fasciotomy\tnm\tnm\t1722\t\nEight hours after fasciotomy\t30.5\t7\t3421\t\nDay 2 after surgery and levothyroxine therapy\t24.4\t6\t1747\t\nOne week after discharge\t1.7\t13\t115\t\nCK creatinine kinase, EU emergency unit, fT4 free thyroxine, nm not measured, TSH thyroid-stimulating hormone\n\n\n\nThe surgery successfully removed the intense pain of our patient’s forearm. However, a new problem surfaced in the postoperative ward, where he started complaining of similar intense pain in both calves, only a few hours after recovering from the forearm fasciotomy. Upon examination of his legs 3 hours after the forearm fasciotomy had been completed, his calf muscles appeared swollen, but soft and there was no clinical sign of compartment syndrome or myxedema. An ultrasound examination of his lower extremities was performed, but showed open deep veins bilaterally, excluding venous thrombosis as a source of the pain. The pain subsequently increased over the next few hours, but responded to elevation and opioid analgesics (5 mg oxycodone intravenously administered every 2 hours for 6 hours). The next morning, 18 hours after the forearm fasciotomy, the pain in his calves was still present but less severe and thyroid hormone replacement therapy was initiated with a levothyroxine dose of 50 μg a day. Over the next few days the pain in his calves gradually subsided, before disappearing completely on day 3 after the surgery. The edema of his forearm muscle also diminished over the next few days and the skin was closed on day 6 after the fasciotomy.\n\nOur patient was followed regularly by an endocrinologist after he was discharged from hospital. His thyroid function stabilized on a substitution regime of 10 μg of liothyronine a day, in addition to 150 μg of levothyroxine 4 days a week and levothyroxine 125 μg the remaining 3 days of the week. Eight months after discharge he was seen by a neurologist. A full neurological examination only revealed normal findings, specifically demonstrating symmetrical and normal power, and normal sensation and function of his hand and wrist.\n\nDiscussion\nHoffmann’s syndrome is a rare condition, and to the best of the authors’ knowledge it has not been previously reported in Scandinavia. Fasciotomy in this setting is even more extraordinary, with only a few published cases [1–5]. In contrast to previously published cases, the compartment that was affected in this case report was the dorsolateral compartment of the forearm, whereas the patients in previous reports all presented with compartment syndromes of tibial compartments. This is probably a reflection of the fact that anterior and lateral compartments of the lower legs are most commonly affected overall [6, 7], making this case report even more unusual.\n\nThe present case report demonstrates that the recognition of a rather clear-cut syndrome, such as acute compartment syndrome, may be obscured when the underlying pathology is misconceived. An acute compartment syndrome rarely occurs in the absence of a physical trauma or conditions which compromise limb circulation. The lack of an obvious triggering cause in the initial diagnostic workup may therefore have delayed the timing of the fasciotomy. Due to our patient’s substantial requirement for morphine analgesics overnight, and the failure of these to adequately resolve the pain in his forearm, it may be argued that the compartment syndrome should have been recognized earlier and the fasciotomy performed accordingly. The amount of skeletal muscle necrosis suffered from a compartment syndrome is directly proportional to the duration of ischemia [8], and time should not be wasted in unnecessary diagnostic workup. On the other hand, no muscle necrosis was found at the time of fasciotomy or during subsequent revisions, indicating that the surgery was, although 16 hours after admission, performed in time.\n\nOur patient most likely suffered from Hoffmann’s syndrome, a rare condition characterized by increased muscular mass, muscle stiffness, proximal muscle weakness, and occasional muscle cramps in the presence of hypothyroidism [9]. Although muscle stiffness and weakness were less pronounced symptoms in the present case, a more focused clinical examination revealed proximal hypertrophy of the calves, upper arms, and shoulders in a patient who denied being physically active (Fig. 2). A muscle biopsy obtained from his forearm at the time of closure of the skin only revealed acute myopathic changes with necrosis and signs of impaired circulation, which were probably caused by the compartment syndrome itself, rather than the endocrine myopathy. Another muscle biopsy obtained simultaneously from the left tensor fascia lata muscle revealed mild, nonspecific myopathic changes with increased fiber size variability and some few internalized nuclei.\nFig. 2 The patient photographed from the back exhibiting proximal hypertrophy of the calves, arms, and shoulders\n\n\n\nThe lower leg seems to be the most common location of compartment syndrome associated with hypothyroidism, with five previously published cases involving fasciotomy of tibial compartments [1–5]. To the best of our knowledge, only one patient with hypothyroid-induced compartment syndrome in the forearm has previously been reported. However, the patient in this previously reported case also presented with acute compartment syndrome of the lower extremities. The previously described bilateral compartment syndrome of the forearms appeared only the day after bilateral lower extremity fasciotomies were performed [5].\n\nAn important aspect of this case report is the use of succinylcholine during the induction of general anesthesia. Succinylcholine is a depolarizing neuromuscular agent, which through competitive inhibition of acetylcholine ultimately leads to relaxation of striated muscle. A well-known side effect of succinylcholine is its ability to induce fasciculations and postoperative myalgia [10]. The exact reason why succinylcholine causes postoperative myalgia is not clearly understood. Suggested mechanisms include muscle fiber damage produced by the shearing forces associated with these fasciculations and the release of potassium from muscle cells. However, no simple correlation between the severity of muscle fasciculations, serum potassium changes, and the development of postoperative myalgia has been proved [10]. Although the relationship between succinylcholine-induced fasciculations and postoperative myalgia remains controversial, it may seem to be a legitimate explanation in this particular case report. Due to pseudohypertrophy of this particular patient’s lower legs, his muscle-rich tibial compartments may have been more susceptible to succinylcholine-induced fasciculations, explaining the findings of painful and clinically swollen calves following the forearm fasciotomy. Muscular edema of the tibial compartments may have been further exacerbated by immobilization and fluid resuscitation.\n\nThe association between hypothyroidism and compartment syndrome was first recognized after the forearm fasciotomy and while our patient was complaining of increasing pain in both calves in the postoperative ward. As the surgical team considered surgical options for his calves as well, an endocrinologist was consulted and hypothyroidism myopathy was introduced as a possible explanation of our patient’s condition. He was treated with elevation of his legs and was given orally administered levothyroxine, after which the pain in his calves diminished within hours, before disappearing completely after a couple of days. The reason for our patient’s quick recovery from pain in his calves was probably due to the elevation of his legs and the metabolism of succinylcholine, rather than levothyroxine treatment alone. The effect of levothyroxine treatment on muscle in hypothyroid myopathy typically emerges within several weeks [11], although messenger ribonucleic acid (mRNA) synthesis in hypothyroid muscular cells has been shown to be dramatically increased within 48 hours [12]. In hindsight, it is speculated whether the use of a non-depolarizing neuromuscular blocking agent for induction of general anesthesia instead of succinylcholine would have prevented the postoperative pain in the calves experienced by our patient. In a worst case scenario, compartment syndromes may have developed in his tibial compartments as well. A similar case report involving a patient with hypothyroidism subjected to bilateral fasciotomy of the tibial compartments followed by upper extremity fasciotomies the next day has previously been reported [5], although it is not clear whether a depolarizing neuromuscular blocking agent was utilized in that particular case.\n\nConclusion\nHoffmann’s syndrome may precipitate a compartment syndrome in the absence of trauma. The present case report highlights the importance of a multidisciplinary approach to complex surgical cases.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthor’s contributions\nEA treated the patient presented and wrote the manuscript under supervision of JD. RJ contributed in the diagnostic workup. TS described the computed tomography and specifically designed Fig. 1. HH analyzed the muscle biopsies. OS anaesthetized the patient and specifically contributed to the discussion on succinylcholine in this case report. All authors contributed to the writing of the manuscript. All authors read and approved the final manuscript.\n\nFunding\n A publication grant was provided from UiT - the Arctic University of Norway`s publication fund.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Thacker AK Agrawal D Sarkari NB Bilateral anterior tibial compartment syndrome in association with hypothyroidism Postgrad Med J 1993 69 817 881 883 10.1136/pgmj.69.817.881 8290438 \n2. Hsu SI Thadhani RI Daniels GH Acute compartment syndrome in a hypothyroid patient Thyroid. 1995 5 4 305 308 10.1089/thy.1995.5.305 7488873 \n3. Hariri N Mousa A Abu-Halimah S Richmond B Bilateral lower extremity anterior compartment syndrome in a severely hypothyroid patient Am Surg 2014 80 12 E337 E338 25513901 \n4. Modi A Amin H Salzman M Morgan F Acute compartment syndrome caused by uncontrolled hypothyroidism Am J Emerg Med 2017 35 6 937.e5 937.e6 10.1016/j.ajem.2016.12.054 \n5. Musielak MC Chae JH Hypothyroid-induced acute compartment syndrome in all extremities J Surg Case Rep 2016 2016 12 rjw215 10.1093/jscr/rjw215 28003319 \n6. Schubert AG Exertional compartment syndrome: review of the literature and proposed rehabilitation guidelines following surgical release Int J Sports Phys Ther 2011 6 2 126 141 21713230 \n7. Gourgiotis S Villias C Germanos S Foukas A Ridolfini MP Acute limb compartment syndrome: a review J Surg Educ 2007 64 3 178 186 10.1016/j.jsurg.2007.03.006 17574182 \n8. Raza H Mahaptra A Acute compartment syndrome in orthopedics: causes, diagnosis and management Adv Orthop 2015 2015 543412 10.1155/2015/543412 25688303 \n9. Lee KW Kim SH Kim KJ Kim SH Kim HY Kim BJ Kim SG Choi DS A rare manifestation of hypothyroid myopathy: hoffmann's syndrome Endocrinol Metab (Seoul) 2015 30 4 626 630 10.3803/EnM.2015.30.4.626 26394732 \n10. Wong SF Chung F Succinylcholine-associated postoperative myalgia Anaesthesia. 2000 55 2 144 152 10.1046/j.1365-2044.2000.055002144.x 10651675 \n11. Argov Z Renshaw PF Boden B Winokur A Bank WJ Effects of thyroid hormones on skeletal muscle bioenergetics. In vivo phosphorus-31 magnetic resonance spectroscopy study of humans and rats J Clin Invest 1988 81 6 1695 1701 10.1172/JCI113508 3384946 \n12. Gustafson TA Markham BE Morkin E Effects of thyroid hormone on alpha-actin and myosin heavy chain gene expression in cardiac and skeletal muscles of the rat: measurement of mRNA content using synthetic oligonucleotide probes Circ Res 1986 59 2 194 201 10.1161/01.RES.59.2.194 3742743\n\n",
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"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D003161:Compartment Syndromes; D000071938:Fasciotomy; D005542:Forearm; D006801:Humans; D007037:Hypothyroidism; D008297:Male; D009135:Muscular Diseases; D010146:Pain; D013974:Thyroxine",
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"title": "Hoffmann's syndrome necessitating forearm fasciotomy: a case report.",
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"abstract": "Descending Necrotizing Mediastinitis (DNM) is the fatal form of mediastinitis and mostly develops as a complication of peritonsillar abscesses or dental-odontogenic infections. The aim of this study is to evaluate clinical and surgical feature of the patients with DNM who were managed in our clinic.\n\n\n\nWe retrospectively evaluated 13 consecutive patients with the diagnosis of DNM between February 2005 and February 2018. All of them had the typical physical appearance, history and radiological findings.\n\n\n\nTen (77%) patients were male, 3 (23%) patients were female with a median age of 48.2 (18-76 years). All patients underwent Cervico-Mediastinal Drainage (CMD) with debridement of the necrotic and infected tissues. Other supplimantary surgical procedures were tube thoracostomy (n = 8), VATS mediastinal drainage (n = 4), tracheostomy (n = 2) and thoracatomy (n = 1). The median time to diagnosis of DNM, tube drainage (inserted after CMD) removal time, tube thoracostomy removal time, lenght of hospital stay were 1.8 (range 1-4) days, 13.6 (range 10-20), 12.6 days (range 10-27) and 21.5 days (range 15-30), respectively. Appropriate and potent antibiotics were used according to the fever-CRP response with the consultation on infectious disease specialist. Two patients were lost due to fulminant sepsis (n = 1) and massive cervical haemorrhage (n = 1). Overall mortality rate was 15%. Complications were recorded in 6 patients (46%).\n\n\n\nThe critical point in the management of DNM is the correct diagnosis, rapid surgical intervention with antibiotherapy and close follow-up for possible complications. We concluded that the combination of minimally invasive management as VATS-tube thoracostomy with CMD is the most appropriate surgical interventions.",
"affiliations": "Faculty of Medicine, Trakya University, Edirne,Turkey. fazliyanik@hotmail.com.;Faculty of Medicine, Trakya University, Edirne,Turkey. altemurk@hotmail.com.;Faculty of Medicine, Trakya University, Edirne,Turkey. yyoruk@trakya.edu.tr.",
"authors": "Yanık|Fazlı|F|;Karamustafaoğlu|Yekta Altemur|YA|;Yoruk|Yener|Y|",
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"keywords": "fatal; infection; mediastinitis; mediastinum",
"medline_ta": "J Infect Dev Ctries",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D004322:Drainage; D005260:Female; D006801:Humans; D008297:Male; D008480:Mediastinitis; D008482:Mediastinum; D008875:Middle Aged; D009336:Necrosis; D012189:Retrospective Studies; D013907:Thoracostomy; D014139:Tracheostomy",
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"title": "Management of a difficult infectional disease: Descending necrotizing mediastinitis.",
"title_normalized": "management of a difficult infectional disease descending necrotizing mediastinitis"
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"abstract": "Avoid prescribing medications that can cause weight gain in overweight and obese patients when possible, use the lowest effective dose when such agents are necessary, and warn patients of this adverse effect so that they can take precautions, such as walking an extra mile a day or giving up that high-calorie latte in the morning.",
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"abstract": "This is the first case of Spiromastigoides asexualis human infection, and it notably gave a false-positive Blastomyces DNA probe laboratory result. We further investigated other Spiromastigoides isolates as a cause of false-positive testing results, their phylogenetic relationship, and their susceptibility profiles to clinically available antifungal agents. Other S. asexualis isolates also resulted in positive Blastomyces DNA probe results, while Spiromastigoides species other than S. asexualis did not.",
"affiliations": "Department of Internal Medicine, Division of Infectious Diseases, University of California-Davis Health, Davis, CA, USA.;Fungus Testing Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.;Fungus Testing Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.;Fungus Testing Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.;Department of Internal Medicine, Division of Infectious Diseases, University of California-Davis Health, Davis, CA, USA grthompson@ucdavis.edu.",
"authors": "Nguyen|Minh-Vu H|MH|;Wiederhold|Nathan P|NP|0000-0002-2225-5122;Cañete-Gibas|Connie|C|;Sanders|Carmita|C|;Thompson|George R|GR|0000-0001-8518-5750",
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"keywords": "Blastomyces\n; DNA probe; Spiromastigoides\n; blastomycosis; false-positive; fungal; fungus; mold; novel; phylogenetic; phylogenetics",
"medline_ta": "J Clin Microbiol",
"mesh_terms": "D000935:Antifungal Agents; D001758:Blastomyces; D001759:Blastomycosis; D015342:DNA Probes; D006801:Humans; D010802:Phylogeny",
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"title": "Spiromastigoides asexualis: Phylogenetic Analysis and Evaluation as a Cause of False-Positive Blastomyces DNA Probe Test Results.",
"title_normalized": "spiromastigoides asexualis phylogenetic analysis and evaluation as a cause of false positive blastomyces dna probe test results"
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"abstract": "BACKGROUND\nWe present a case of CVID complicated by granulomatous interstitial lung disease (GLILD). This patient clinical course was further complicated by COVID-19 infection. This is only the 2nd known case report of COVID 19 in CVID with GLILD. The clinical course and outcome of COVID 19 infection with common variable immunodeficiency (CVID) and GLILD is not well known.\n\n\nMETHODS\nOur patient met the clinical features of CVID secondary to low IgG/IgA, recurrent infections, and failure to respond to pneumococcal vaccination. He was treated with monthly maintenance IVIG therapy. Our patient also was diagnosed with co-existing GLILD that despite IVIG treatment was progressing. The patient needed to be started on Rituxan and Mycophenolate mofetil to achieve control but unfortunately became infected with COVID19 delaying his treatment for GLILD. Our patient only suffered from mild COVID 19 infection and was able to make antibodies to this. We believe severe infection was avoided as his CVID was well controlled with IVIG therapy despite progression of his granulomatous interstitial lung disease.\n\n\nCONCLUSIONS\nIn conclusion, our patient with CVID with co-existing biopsy proven granulomatous interstitial lung disease despite being very high risk for severe COVID 19 infections only had mild infection. This was believed to be due to well controlled CVID with IVIG therapy.",
"affiliations": "Division of Rheumatology and Immunology, Department of Medicine, University of Tennessee Health Sciences Center, Room G326, 956 Court Ave, TN 38163, Memphis, United States. dpattana@uthsc.edu.;Division of Allergy and Clinical Immunology, Le Bonheur Children's Hospital, University of Tennessee Health Sciences Center, TN 38163, Memphis, United States.;Division of Allergy and Clinical Immunology, Le Bonheur Children's Hospital, University of Tennessee Health Sciences Center, TN 38163, Memphis, United States.",
"authors": "Pattanaik|Debendra|D|;Ritter|Shaunah|S|;Fahhoum|Joseph|J|",
"chemical_list": null,
"country": "England",
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"fulltext": "\n==== Front\nAllergy Asthma Clin Immunol\nAllergy Asthma Clin Immunol\nAllergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology\n1710-1484\n1710-1492\nBioMed Central London\n\n600\n10.1186/s13223-021-00600-y\nCase Report\nCommon variable immunodeficiency (CVID) with granulomatous interstitial lung disease (GLILD) and SARS COVID-19 infection: case report and review of literature\nPattanaik Debendra dpattana@uthsc.edu\n\n1\nRitter Shaunah sritter3@uthsc.edu\n\n2\nFahhoum Joseph memphisallergy@msn.com\n\n2\n1 grid.267301.1 0000 0004 0386 9246 Division of Rheumatology and Immunology, Department of Medicine, University of Tennessee Health Sciences Center, Room G326, 956 Court Ave, TN 38163 Memphis, United States\n2 grid.267301.1 0000 0004 0386 9246 Division of Allergy and Clinical Immunology, Le Bonheur Children’s Hospital, University of Tennessee Health Sciences Center, TN 38163 Memphis, United States\n26 9 2021\n26 9 2021\n2021\n17 984 5 2021\n8 9 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nWe present a case of CVID complicated by granulomatous interstitial lung disease (GLILD). This patient clinical course was further complicated by COVID-19 infection. This is only the 2nd known case report of COVID 19 in CVID with GLILD. The clinical course and outcome of COVID 19 infection with common variable immunodeficiency (CVID) and GLILD is not well known.\n\nCase presentation\n\nOur patient met the clinical features of CVID secondary to low IgG/IgA, recurrent infections, and failure to respond to pneumococcal vaccination. He was treated with monthly maintenance IVIG therapy. Our patient also was diagnosed with co-existing GLILD that despite IVIG treatment was progressing. The patient needed to be started on Rituxan and Mycophenolate mofetil to achieve control but unfortunately became infected with COVID19 delaying his treatment for GLILD. Our patient only suffered from mild COVID 19 infection and was able to make antibodies to this. We believe severe infection was avoided as his CVID was well controlled with IVIG therapy despite progression of his granulomatous interstitial lung disease.\n\nConclusion\n\nIn conclusion, our patient with CVID with co-existing biopsy proven granulomatous interstitial lung disease despite being very high risk for severe COVID 19 infections only had mild infection. This was believed to be due to well controlled CVID with IVIG therapy.\n\nKeywords\n\nCVID\nGLILD\nCOVID-19\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nImmunodeficiency and interstitial lung disease are mentioned as risk factors for unfavorable outcome in COVID-19 infection [1, 2]. However, there is limited data on the outcome of COVID-19 infection in this subset of patients especially with CVID. There are cases of fatal outcome in CVID patients who had coexisting underlying lung disease and other comorbidities [3, 4]. GLILD is an uncommon complication in CVID patients leading to progressive lung disease [5]. Our case shows an example of a patient with CVID complicated by granulomatous interstitial lung disease who became infected with COVID19.\n\nCase\n\nA 27-year-old Caucasian male patient was initially evaluated in the allergy and immunology clinic in January 2019 for immunodeficiency. His initial symptoms started in June of 2017 when the patient started having recurrent episodes of pneumonia that were treated by his primary care physician (PCP). Incidentally at this time he was found to also have thrombocytopenia. He complained primarily of recurrent productive cough with green discharge over the past 1½ years. His other symptoms included: intermittent headaches, sinus pressure, nasal congestion, rhinorrhea, intermittent diarrhea, fatigue, and loss of smell but denied fever, chills, and night sweats. The patient had initially lost around 10–11 pounds at the start of his disease course. His family history was pertinent for a brother who also had thrombocytopenia and died from a brain aneurysm. Secondary to the above the patient was referred to hematology for further work up. Hematology completed further investigation during the Summer of 2017. This included monitoring of his platelet counts over a 12 month which showed varying levels between 91 and 108 × 109/l. The rest of his CBC with differential, complete metabolic panel and urinalysis were normal. Quantitative immunoglobulin panels were completed four times over an additional 12-month period revealing the following: IgG 256–308 mg/dl (700–1600), IgM 9–25 (40–230), IgA 23–33 (70–400). A CT chest and abdomen revealed mediastinal and upper abdominal lymphadenopathy, splenomegaly, and multiple pulmonary nodules. Secondary, to his hypogammaglobulinemia he was vaccinated with pneumovax by the hematologist which included 2 doses, 1 month apart in May 2018 and June 2018. His findings on imaging made hematology concerned about tuberculosis, fungal infections, malignancy, and granulomatous disease such as sarcoidosis as a potential underlying cause. He was referred to pulmonary clinic in July 2018 for a lung biopsy. During his work up pulmonary function tests showed moderate reduction of airflow (FEV1/FVC: 59%), normal vital capacity and moderate reduction of diffusion capacity. These findings were certainly consistent with obstructive lung disease. He underwent bronchoscopy and ultrasound guided endobronchial lymph node biopsy twice in the summer of 2018. A Bronchoalveolar lavage (BAL) with multiple node biopsies were negative for bacterial, fungal and TB as a cause of lung disease. Testing was also negative for malignancy. He was started on fluticasone furoate, umeclidinium and vilanterol for further management with improvement in FEV1/FVC ratio (85%). However, part of his work up included an aspergillus galactomannan test which ended up being positive leading to pulmonary to start him on oral isavuconazonium sulfate to treat him for aspergillus infection. His antifungal treatment was continued for 5 weeks but was stopped in November 2018 secondary to side effects (elevated liver enzymes, nausea, and vomiting). Upon his follow up a repeat CT chest was ordered in December 2018 showing progression of multifocal nodularity in his lung and unchanged mediastinal lymphadenopathy. (Fig. 1a, b). Secondary to this he underwent VATS guided lung biopsy of his superior right lower lung segment in January 2019.Fig. 1 a CT chest showing scattered nodular (green arrow) and reticular densities (magenta arrow). b CT chest showing bilateral hilar and subcarinal lymphadenopathy (arrows)\n\nWhen the patient presented to A/I clinic a physical examination showed the following: vital signs: 110/80, P: 64/minute, temp: 97, RR: 18/minute. ENT exam showed bilateral swollen pale nasal turbinate with light yellow drainage. The rest of his physical examination was unremarkable. Repeat laboratory testing was ordered in January 2019 and showed a platelet count of 96 K. The following tests were all negative CMP, urinalysis, stool ova and parasites, and HIV test. An Immunoglobulin panel showed an IgM 10 (40–230 mg/dl), IgG 520 (700–1600 mg/dl), IgA 26 (70–400 mg/dl), IgE < 2 (0–158 mg/dl). Lymphocyte subsets are as followed: absolute lymphocyte: 1126 (1000–4000), CD3: 935 (960–2600) [83% (61–84)], CD4: 586 (540–1660) [52% (32–60)], CD8: 304 (270–930) [27 (13–40%)], CD19: 79 (122–632) [7% (3–22)], CD16 + 56: 90 (70–480) [8% (3–22)]. As the next step of work up a lymphocyte mitogen screen showed a low to PHA and a normal Con A and Pokeweed Mitogen. A sinus X ray was remarkable for left maxillary sinus disease showing mucosal thickening. Despite being vaccinated the patient had poor pneumococcal antibody titers with only 2/14 ≥ 1.3 μg/ml being responsive. His tetanus antibody titer was in the protective range of 1.3. The patient eventually did have a lung biopsy that showed lymphoid hyperplasia with interstitial fibrosis, patchy foci of organizing pneumonia, rare giant cells/histiocytes, acute bronchopneumonia and occasional fibrin exudates. Overall, the interstitial findings are compatible with the CVID-related interstitial lung disease, granulomatous lymphocytic interstitial lung disease (GLILD). Given the extensive lymphoid component, MALT lymphoma was considered; however, the immunohistochemistry profile, flow cytometry and molecular studies (per report) show no evidence of a clonal B-cell process. (Fig. 2). Based on these findings, allergy/immunology service confirmed the diagnosis of CVID with coexisting immune thrombocytopenia and GLILD. The patient had been started on treatment with IVIG 30 g every 4 weeks based on his initial immunoglobulins by hematology and this was continued by us. We obtained repeat quantitative IgG after therapy and the level was 600 (600–1640 mg/dl) on 10/1/2019. We subsequently increase his IVIG dose to 50 g every 4 weeks because of decreasing lung function and decreased platelet count. The patient currently remains infection free since November 2018. His follow up chest X ray and CT chest in January 2020 showed further widespread lymphadenopathy and nodular lung densities. Allergy service referred him to rheumatology to begin treatment with Rituximab and mycophenolate mofetil for GLILD. While waiting for treatment with Rituxan, he developed high grade fever, headache, and body ache. He subsequently tested positive for COVID 19 (RT-PCR) through nasal swab. He slowly recovered without any complication at home. Of note the patient did have positive SAR-Cov-2 total antibody test: 207.3 [(0–0.9 index) (Roche ECLIA)] about 10 weeks after he tested positive for COVID-19. The patient eventually was able to start Rituximab infusion of 375 mg/m2 weekly for 4 weeks and completed four cycles of therapy without complication. He is now just on maintenance mycophenolate mofetil 1 g and monthly IVIG and is doing well.Fig. 2 Lung biopsy showing lymphoid hyperplasia (arrows) and giant cell (inset)\n\nDiscussion\n\nOur patient fulfilled the diagnostic criteria for CVID [6]. He suffered recurrent pulmonary and sinus infections accompanied by marked decrease in IgG and IgA level as well as poor vaccination response to pneumovax 23. GLILD is a distinct clinical entity with unique radiologic and histological features seen in 20% of patients with CVID. GLILD is associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and excluded [5]. 21% of CVID patients complicated by GLILD had damaging mutation in genes e.g., TNFRSF13B, CTLA4, KMT2D, BIRC4 known to cause CVID [8]. The diagnosis is usually made by CT chest followed by an open lung biopsy [5] However, CT findings are not specific and include pulmonary nodules, ground-glass opacities, hilar and/or mediastinal lymphadenopathy, and reticulation that be seen in other etiologies [5]. That is why an open lung biopsy is essential to exclude other infectious and malignant conditions. Histologic findings with GLILD include granulomatous inflammation, peribronchiolar lymphoid proliferation, interstitial lymphoid proliferation, with a CD4 + T-Cell predominance. We were able to confirm that he had GLILD based on his prior diagnosis of CVID and CT chest and histologic findings. There was a delay in diagnosis of CVID and GLILD for about year and half until he was seen by allergy and immunology. Such delay in diagnosis is not uncommon for CVID cases [7]. Currently there is no consensus on the treatment of GLILD aside from continuing IVIG therapy, though corticosteroids have been used in the past [5]. Recent literature does support combination chemotherapy using Rituximab with azathioprine or mycophenolate mofetil as the first line therapy [8]. A summary of treatment regimens is summarized in Table 1. Based on the literature above which is the largest cohort of CVID patient with GLILD, we decided to treat using rituximab and mycophenolate mofetil without corticosteroid. There is risk of opportunistic infection with immunosuppressive treatment. Pneumonia and opportunistic infection e.g., pneumocystis, nontuberculous mycobacteria, varicella zoster and possibly progressive multifocal leukoencephalopathy have been reported [5, 8].Table 1 Treatment of CVID-GLILD with immunosuppressive therapy\n\nAgent\tRTX [17]\tRTX + AZA [8]\tRTX + MMF [8, 18]\t\nNumber of patients\t3\t29\t15\t\nRegimen used\t375 mg/m2 weekly × 4, then every 6 months\tRTX: 375 mg/m2 weekly × 4, then every 4–6 months + AZA: 1–2 mg/kg/day\tRTX: 375 mg/m2 weekly × 4, then every 4–6 months + MMF: 250–1000 mg twice daily (N = 14)\t\nRTX: 1 g × 2 dose 1 month apart + MMF: 1–2 g/day (N = 1)\t\nDuration of follow up\t24 months\t16 months\t16 months\t\nOutcome\tImprovement in CT chest and PFT\tImprovement in CT chest and PFT, death = 1, relapse = 6\tImprovement in CT chest and PFT, death = 1, relapse = 3\t\nAdverse events\tNone reported\tReversible hepatotoxicity, intolerance, pneumonia\tPneumonia\t\nAZA azathioprine, MMF mycophenolate mofetil, RTX rituxan\n\nCOVID19 is known to be high risk to patients with comorbid conditions such as chronic lung disease, age > 65, and underlying immunodeficiency state etc. [1]. Patients with interstitial lung disease like ours are at an increased risk of hospitalization and ICU care [2]. Our patient was possibly at an even higher risk given the history of CVID and coexisting interstitial lung disease.\n\nThere is limited data on the outcome of COVID-19 infection in CVID patients based on case reports and small case series. Ho et al. looked at 16 patients with primary immunodeficiency (PID) who had COVID-19 infection and 9 of them were CVID patients [3]. Patients with PID can have a range of disease severity from mild to severe infection. However, a portion in this study showed that 25% (4/16) died making the mortality rate in PID higher compared to the general population. In the same study, 2/16 patients with CVID and COVID19 infection died but each had associated lung disease such as bronchiectasis and interstitial lung disease that was unspecified [3]. The patients who were on maintenance IVIG replacement therapy and those without preexisting autoimmune/inflammatory disease had better outcomes. Two other published case reports showed successful recovery from COVID-19 infection in patients with PID. Both patients had bronchiectasis and happened to receive additional IVIG during hospitalization. The authors attributed their recovery to having stable IgG level with their maintenance IVIG treatment prior to infection [9, 10] However another subject with CVID had a fatal outcome from COVID-19 infection from secondary bacterial infection despite multiple courses of IVIG infusion while being hospitalized. This patient was off their maintenance IVIG therapy with low IgG levels upon infection and hospitalization [4]. The comparison of these cases shows importance of having good control of CVID prior to infection with COVID19. Our patient did well as he had uninterrupted IVIG infusion throughout the whole time and normal IgG levels. In a small study IVIG administration was given to patients without CIVD who had severe COVID-19 infection and had not responded to initial treatment and showed decrease mortality [11]. Some of the current IVIG products in United States (Gammunex-C 10% and Flebogamma 5% DIF) have cross reacting antibodies against SARS-CoV-2 from other coronavirus families e.g., SARS-CoV and MERS-CoV [12]. The authors suggest presence of cross-reacting SARS-CoV-2 antibodies along with immunomodulatory and anti-inflammatory effect of IVIG may help severe COVID-19 infection [12].\n\nLike our patient, some CVID patients mount SARS-CoV-2 detectable antibody responses though the duration and significance of it is not clear at this point per that author [3]. It would be difficult to tell without prior testing if our patient had cross reacting antibodies.\n\nPatients with CVID may be at a higher a risk for severe disease compared to patients with X linked agammaglobulinemia (XLA). In a small case series involving 7 patients (5 with CVID and 2 with agammaglobulinemia) Quinti et al. [13] noted that CVID patients had a more severe disease course compared to the XLA group despite having similar baseline and maintenance Ig levels. This is suspected to be due to lack of B lymphocytes in patients with XLA vs having dysfunctional B lymphocytes in CVID patients. CVID patients were also noted to have higher levels of inflammatory markers e.g., C-reactive protein, fibrinogen, D-dimer, IL-6, IL-8, and TNF-α compared to XLA patients [3]. The Bruton Tyrosine Kinase (BTK) protein mediates signaling of the viral ssRNA-sensing toll-like receptor pathway [14]. Increase in monocyte BTK activation was found during severe COVID-19 infection and BTK inhibitors could potentially be used to treat severe COVID-19 related inflammation and lung injury [15, 16]. It is likely B lymphocytes play a role in COVID-19 induced inflammation [13].\n\nConclusion\n\nIn conclusion our CVID patient whose course is complicated with GLILD recovered from COVID-19 infection at home uneventfully compared to other cases with comorbid pulmonary conditions. A recent abstract published showed a patient with CVID and GLILD on infliximab had a mild disease course like our patient [16]. This further supports that it is likely that regular maintenance IVIG infusion may have prevented a bad outcome as well as immunomodulating medications helping prevention of the cytokine storm [16]. Of note our patient was also able to generate significant SARS-COVID-19 antibody response following infection. However, a general conclusion of the excellent outcome of COVID-19 infection in CVID with GLILD patients cannot be made just based on 2 case reports and need further study.\n\nAbbreviations\n\nSARS Severe acute respiratory syndrome\n\nCOVID-19 COronaVIrusDisease-2019\n\nCVID Common variable immunodeficiency\n\nGLILD Granulomatous interstitial lung disease\n\nPID Primary immunodeficiency\n\nXLA X linked agammaglobulinemia\n\nIVIG Intravenous immunoglobulins\n\nBTK Bruton tyrosine kinase\n\nICU Intensive care unit\n\nMALT Mucosa associated lymphoid tissue\n\nTB Tuberculosis\n\nBAL Bronchoalveolar lavage\n\nFEV Forced expiratory volume\n\nFVC Forced vital capacity\n\nVATS Video assisted thoracoscopic surgery\n\nRT-PCR Reverse transcription polymerase chain reaction\n\nRTX Rituxan\n\nAZA Azathioprine\n\nMMF Mycophenolate mofetil\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nDP: contributed to writing the case and discussion, SR: contributed to writing the case and discussion, JF: contributed to writing the case and discussion. All authors have read and approved the final manuscript.\n\nFunding\n\nNo relevant funding to declare.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Your health: people with certain medical conditions and risks of severe Covid-19 infections. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Accessed on 2 May 2021.\n2. Podolanczuk AJ Richeldi L COVID-19 and interstitial lung disease: keep them separate Am J Respir Crit Care Med 2020 202 12 1614 1616 10.1164/rccm.202010-3918ED 33113338\n3. Ho HE Mathew S Peluso MJ Cunningham-Rundles C Clinical outcomes and features of COVID-19 in patients with primary immunodeficiencies in New York City J Allergy Clin Immunol Pract 2020 S2213–2198 20 31102 31108\n4. Mullur J Wang A Feldweg A A fatal case of coronavirus disease 2019 in a patient with common variable immunodeficiency Ann Allergy Asthma Immunol 2021 126 1 90 92 10.1016/j.anai.2020.08.017 32818593\n5. Hurst JR Verma N Lowe D Baxendale HE British Lung Foundation/United Kingdom Primary Immunodeficiency Network Consensus Statement on the definition, diagnosis, and management of granulomatous-lymphocytic interstitial lung disease in common variable immunodeficiency disorders J Allergy Clin Immunol Pract 2017 5 4 938 945 10.1016/j.jaip.2017.01.021 28351785\n6. Bonilla FA Barlan I Chapel H Costa-Carvalho BT International consensus document (ICON): common variable immunodeficiency disorders J Allergy Clin Immunol Pract 2016 4 1 38 59 10.1016/j.jaip.2015.07.025 26563668\n7. Cunningham-Rundles C Bodian C Common variable immunodeficiency: clinical and immunological features of 248 patients Clin Immunol 1999 92 1 34 48 10.1006/clim.1999.4725 10413651\n8. Verbsky JW Hintermeyer MK Simpson PM Feng M Barbeau J Rao N Cool CD Sosa-Lozano LA Baruah D Hammelev E Busalacchi A Rymaszewski A Woodliff J Chen S Bausch-Jurken M Routes JM Rituximab, and antimetabolite treatment of granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency J Allergy Clin Immunol 2021 147 2 704 712.e17 10.1016/j.jaci.2020.07.021 32745555\n9. Aljaberi R Wishah K Positive outcome in a patient with coronavirus disease 2019 and common variable immunodeficiency after intravenous immunoglobulin Ann Allergy Asthma Immunol 2020 125 3 349 350 10.1016/j.anai.2020.06.006 32505720\n10. Fill L Hadney L Graven K Persaud R Hostoffer R The clinical observation of a patient with common variable immunodeficiency diagnosed as having coronavirus disease 2019 Ann Allergy Asthma Immunol 2020 125 1 112 114 10.1016/j.anai.2020.04.033 32387167\n11. Gharebaghi N Nejadrahim R Mousavi SJ The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus disease 2019: a randomized placebo-controlled double-blind clinical trial BMC Infect Dis 2020 20 786 10.1186/s12879-020-05507-4 33087047\n12. Díez JM Romero C Gajardo R Currently available intravenous immunoglobulin contains antibodies reacting against severe acute respiratory syndrome coronavirus 2 antigens Immunotherapy 2020 12 8 571 576 10.2217/imt-2020-0095 32397847\n13. Quinti I Lougaris V Milito C A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia J Allergy Clin Immunol 2020 146 1 211 213 10.1016/j.jaci.2020.04.013 32333914\n14. Roschewski M Lionakis MS Sharman JP Roswarski J Goy A Monticelli MA Inhibition of Bruton tyrosine kinase in patients with severe COVID-19 Sci Immunol 2020 10.1126/sciimmunol.abd0110 32503877\n15. Treon SP Castillo JJ Skarbnik AP Soumerai JD Ghobrial IM Guerrera ML The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19-infected patients Blood 2020 135 1912 1915 10.1182/blood.2020006288 32302379\n16. Chang A case of mild COVID19 infection in a teenager with common variable immunodeficiency and granulomatous interstitial lung disease on replacement immunoglobulin and infliximab JACI Pract 2021 147 2 AB66\n17. Cereser L De Carli R Girometti R De Pellegrin A Reccardini F Frossi B De Carli M Efficacy of rituximab as a single-agent therapy for the treatment of granulomatous and lymphocytic interstitial lung disease in patients with common variable immunodeficiency J Allergy Clin Immunol Pract 2019 7 3 1055 1057.e2 10.1016/j.jaip.2018.10.041 30408616\n18. Pecoraro A Crescenzi L Galdiero MR Marone G Rivellese F Rossi FW de Paulis A Genovese A Spadaro G Immunosuppressive therapy with rituximab in common variable immunodeficiency Clin Mol Allergy 2019 6 17 9 10.1186/s12948-019-0113-3\n\n",
"fulltext_license": "CC BY",
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"journal": "Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology",
"keywords": "COVID-19; CVID; GLILD",
"medline_ta": "Allergy Asthma Clin Immunol",
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"title": "Common variable immunodeficiency (CVID) with granulomatous interstitial lung disease (GLILD) and SARS COVID-19 infection: case report and review of literature.",
"title_normalized": "common variable immunodeficiency cvid with granulomatous interstitial lung disease glild and sars covid 19 infection case report and review of literature"
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"abstract": "To develop and validate clinical risk prediction tools for neonatal abstinence syndrome (NAS).\n\n\n\nWe developed prediction models for NAS based on a set of 30 demographic and antenatal exposure covariates collected during pregnancy. Data (outpatient prescription, vital, and administrative records), were obtained from enrollees in the Tennessee Medicaid Program from 2009 to 2014. Models were created using logistic regression and backward selection based on improvement in the Akaike information criterion, and internally validated using bootstrap cross-validation.\n\n\n\nA total of 218 020 maternal and infant dyads met inclusion criteria, of whom 3208 infants were diagnosed with NAS. The general population model included age, hepatitis C virus infection, days of opioid used by type, number of cigarettes used daily, and the following medications used in the last 30 day of pregnancy: bupropion, antinausea medicines, benzodiazepines, antipsychotics, and gabapentin. Infant characteristics included birthweight, small for gestational age, and infant sex. A high-risk model used a smaller number of predictive variables. Both models discriminated well with an area under the curve of 0.89 and were well-calibrated for low-risk infants.\n\n\n\nWe developed 2 predictive models for NAS based on demographics and antenatal exposure during the last 30 days of pregnancy that were able to risk stratify infants at risk of developing the syndrome.",
"affiliations": "Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN; Department of Health Policy, Vanderbilt University Medical Center, Nashville, TN; Mildred Stahlman Division of Neonatology, Vanderbilt University Medical Center, Nashville, TN. Electronic address: stephen.patrick@vanderbilt.edu.;Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN.;Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN.;Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN.;Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN.;Department of Health Policy, Vanderbilt University Medical Center, Nashville, TN.;Department of Health Policy, Vanderbilt University Medical Center, Nashville, TN.;Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN; Department of Health Policy, Vanderbilt University Medical Center, Nashville, TN.",
"authors": "Patrick|Stephen W|SW|;Slaughter|James C|JC|;Harrell|Frank E|FE|;Martin|Peter R|PR|;Hartmann|Katherine|K|;Dudley|Judith|J|;Stratton|Shannon|S|;Cooper|William O|WO|",
"chemical_list": "D000700:Analgesics; D000932:Antiemetics; D014150:Antipsychotic Agents; D000077444:Smoking Cessation Agents; D016642:Bupropion; D001569:Benzodiazepines; D000077206:Gabapentin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpeds.2020.10.030",
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"issn_linking": "0022-3476",
"issue": "229()",
"journal": "The Journal of pediatrics",
"keywords": null,
"medline_ta": "J Pediatr",
"mesh_terms": "D000328:Adult; D000700:Analgesics; D000932:Antiemetics; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D016642:Bupropion; D005260:Female; D000077206:Gabapentin; D006526:Hepatitis C; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D008297:Male; D008423:Maternal Age; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D009357:Neonatal Abstinence Syndrome; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D011247:Pregnancy; D012189:Retrospective Studies; D018570:Risk Assessment; D017678:Sex Distribution; D012907:Smoking; D000077444:Smoking Cessation Agents; D055815:Young Adult",
"nlm_unique_id": "0375410",
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"pages": "154-160.e6",
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"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D023361:Validation Study",
"references": "32364857;22525931;31576022;24248468;25927272;22546608;26427919;16760444;22291123;23106926;29572288;25869370;28768628;30091969;25975601;31262946;28465360;21142534;25913111;30514781",
"title": "Development and Validation of a Model to Predict Neonatal Abstinence Syndrome.",
"title_normalized": "development and validation of a model to predict neonatal abstinence syndrome"
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"abstract": "We report the success of tardive electroconvulsive therapy in a case of loxapine malignant syndrome with catatonia. Loxapine and its metabolites were measured in biological samples by liquid chromatography coupled to tandem mass spectrometry. Genes were studied by sequencing and quantitative polymerase chain reaction (PCR). Plasmatic drug concentrations showed a supratherapeutic concentration of loxapine with a very low 8-hydroxyloxapine/loxapine ratio (range from 0.32 to 0.66, normal value>2 for 100mg) and a very long elimination half-life of loxapine (half-life>140h, normal value from 1 to 4hours). We tried to explain this kinetics by exploring the main pharmacogenes implicated in the metabolism of loxapine. No genetic abnormality for CYP1A2 was observed. The study of associated treatments showed the potential contribution of valproate. Pharmacokinetics and pharmacogenetics investigations revealed a blockade of the CYP1A2 metabolic pathway without genetic abnormalities, probably due to valproate co-medication. Toxicological monitoring of loxapine and its metabolites helped to explain the persistence of symptoms and to adapt the therapeutic management.",
"affiliations": "Toxicology laboratory, department of medical pharmacology and toxicology, Lapeyronie hospital, CHRU of Montpellier, 34295 Montpellier cedex 5, France. Electronic address: j-descoeur@chu-montpellier.fr.;Toxicology laboratory, department of medical pharmacology and toxicology, Lapeyronie hospital, CHRU of Montpellier, 34295 Montpellier cedex 5, France.;Department of anesthesia, hôpital de la colombière, CHU of Montpellier, 34295 Montpellier, France.;Department of adult psychiatry, hôpital de la colombière, CHU of Montpellier, 34295 Montpellier, France.;Toxicology laboratory, department of medical pharmacology and toxicology, Lapeyronie hospital, CHRU of Montpellier, 34295 Montpellier cedex 5, France; University of Montpellier, 34000 Montpellier, France.;University of Montpellier, 34000 Montpellier, France; Department of critical care, Lapeyronie university hospital, 34295 Montpellier, France.;Toxicology laboratory, department of medical pharmacology and toxicology, Lapeyronie hospital, CHRU of Montpellier, 34295 Montpellier cedex 5, France; University of Montpellier, 34000 Montpellier, France; UMR 5569 hydrosciences, 34090 Montpellier, France.",
"authors": "Descoeur|Juliette|J|;Philibert|Laurent|L|;Chalard|Kevin|K|;Attal|Jérôme|J|;Petit|Pierre|P|;Klouche|Kada|K|;Olivier|Mathieu|M|",
"chemical_list": "D014150:Antipsychotic Agents; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D008152:Loxapine",
"country": "France",
"delete": false,
"doi": "10.1016/j.therap.2017.03.003",
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"issn_linking": "0040-5957",
"issue": "72(6)",
"journal": "Therapie",
"keywords": "Electroconvulsive therapy; Loxapine; Neuroleptic malignant syndrome; Pharmacocinétique; Pharmacogenetics; Pharmacogénétique; Pharmacokinetics; Phenoconversion; Phénoconversion; Sismothérapie; Syndrome malin des neuroleptiques",
"medline_ta": "Therapie",
"mesh_terms": "D014150:Antipsychotic Agents; D002853:Chromatography, Liquid; D019388:Cytochrome P-450 CYP1A2; D004565:Electroconvulsive Therapy; D005260:Female; D006207:Half-Life; D006801:Humans; D008152:Loxapine; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome",
"nlm_unique_id": "0420544",
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"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Success of tardive electroconvulsive therapy sessions after loxapine-induced malignant syndrome in the context of very poor metabolisation.",
"title_normalized": "success of tardive electroconvulsive therapy sessions after loxapine induced malignant syndrome in the context of very poor metabolisation"
} | [
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"companynumb": "PHHY2015FR046766",
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"activesubstancename": "LOXAPINE"
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"abstract": "To describe a case of pachychoroid disease most compatible with central serous chorioretinopathy (CSC) presented with a large relapsing retinal pigment epithelial detachment (PED) associated with only a small amount of subretinal fluid (SRF) in the background of macular drusen in an elderly patient mimicking neovascular age-related macular degeneration (AMD).\nThis was a review of 32 months of the clinical course and findings on multimodal imaging including fundus photography, optical coherence tomography, fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), and optical coherence tomography angiography (OCTA).\nA large relapsing PED sometimes with small amount of SRF at its apex was found in the background of macular drusen in the right eye of a 63-year-old Thai woman. The relapses of the PED showed an apparent association with recent steroid exposure. Multimodal imaging demonstrated the characteristics of pachychoroid diseases with pachyvessels and choroidal hyperpermeability. The PED and SRF responded well to anti-vascular endothelial growth factor (anti-VEGF) therapy, especially aflibercept, but could also be spontaneously resolved without anti-VEGF. No evidence of choroidal neovascularization or polyps could be identified by serial FFA, ICGA, and OCTA even when the retinal pigment epithelium was completely flat with no obscuration by PED.\nA large PED with little SRF could present signs of CSC. This clinical presentation could be confused with neovascular AMD, and multimodal retinal imaging was crucial to guide correct diagnosis and management.",
"affiliations": "Department of Ophthalmology, Chulabhorn Hospital, Chulabhorn Royal Academy, Bangkok, Thailand.;Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.",
"authors": "Kaseewat|Thachpacha|T|;Phasukkijwatana|Nopasak|N|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/JOCO.JOCO_215_20",
"fulltext": "\n==== Front\nJ Curr Ophthalmol\nJ Curr Ophthalmol\nJCO\nJournal of Current Ophthalmology\n2452-2325\nWolters Kluwer - Medknow India\n\nJCO-33-82\n10.4103/JOCO.JOCO_215_20\nCase Report\nNon-Neovascular Pachychoroid Disease Mimicking Exudative Age-Related Macular Degeneration\nKaseewat Thachpacha 1\nPhasukkijwatana Nopasak 2\n1 Department of Ophthalmology, Chulabhorn Hospital, Chulabhorn Royal Academy, Bangkok, Thailand\n2 Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand\nAddress for correspondence: Nopasak Phasukkijwatana, Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wang Lang Road, Bangkoknoi, Bangkok 10700, Thailand. E-mail: nopasak.sioph@gmail.com\nJan-Mar 2021\n26 3 2021\n33 1 8287\n26 5 2020\n28 6 2020\n22 7 2020\nCopyright: © 2021 Journal of Current Ophthalmology\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nPurpose:\n\nTo describe a case of pachychoroid disease most compatible with central serous chorioretinopathy (CSC) presented with a large relapsing retinal pigment epithelial detachment (PED) associated with only a small amount of subretinal fluid (SRF) in the background of macular drusen in an elderly patient mimicking neovascular age-related macular degeneration (AMD).\n\nMethods:\n\nThis was a review of 32 months of the clinical course and findings on multimodal imaging including fundus photography, optical coherence tomography, fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), and optical coherence tomography angiography (OCTA).\n\nResults:\n\nA large relapsing PED sometimes with small amount of SRF at its apex was found in the background of macular drusen in the right eye of a 63-year-old Thai woman. The relapses of the PED showed an apparent association with recent steroid exposure. Multimodal imaging demonstrated the characteristics of pachychoroid diseases with pachyvessels and choroidal hyperpermeability. The PED and SRF responded well to anti-vascular endothelial growth factor (anti-VEGF) therapy, especially aflibercept, but could also be spontaneously resolved without anti-VEGF. No evidence of choroidal neovascularization or polyps could be identified by serial FFA, ICGA, and OCTA even when the retinal pigment epithelium was completely flat with no obscuration by PED.\n\nConclusions:\n\nA large PED with little SRF could present signs of CSC. This clinical presentation could be confused with neovascular AMD, and multimodal retinal imaging was crucial to guide correct diagnosis and management.\n\nAge-related macular degeneration\nAnti-vascular endothelial growth factors\nCentral serous chorioretinopathy\nPachychoroid\nPigment epithelial detachment\n==== Body\nINTRODUCTION\n\nThe pachychoroid disease spectrum (PDS) is a group of retinochoroidal disorders that share common distinctive choroidal findings identified with multimodal retinal imaging. These choroidal characteristics include focal or diffuse choroidal thickening associated with dilated Haller's layer vessels (termed “pachyvessels”) with thinning of the overlying inner choroid and choroidal hyperpermeability on indocyanine green angiography (ICGA). The PDS includes pachychoroid pigment epitheliopathy, central serous chorioretinopathy (CSC), pachychoroid neovasculopathy, polypoidal choroidal vasculopathy, focal choroidal excavation, and peripapillary pachychoroid syndrome.1234\n\nRetinal pigment epithelial detachment (PED) is a common finding not only in neovascular age-related macular degeneration (AMD) but also in PDS such as CSC. Sometimes, it could be difficult to confidently differentiate between vascularized and non-vascularized PED, especially in elderly patients with large serous PED associated with minimal subretinal fluid (SRF) in the background of macular drusen. Such patients were often assumed to have occult Type 1 neovascularization (NV) not detected by fundus angiography. We reported a unique case of relapsing non-neovascular large serous PED with minimal SRF as a presenting sign of CSC as opposed to neovascular AMD, confirmed by optical coherence tomography angiography (OCTA), fundus fluorescein angiography (FFA), and ICGA. This clinical presentation could be spontaneously resolved without anti-vascular endothelial growth factor (anti-VEGF) therapy.\n\nCASE REPORT\n\nA 63-year-old Thai female presented with blurry vision affecting the right eye for 1 month. Informed consent to use images for academic publication was obtained from the patient. Her underlying diseases included hypertension, dyslipidemia, and chronic bilateral sacroiliac joint pain. She had received 20 mg of triamcinolone injections into both of her sacroiliac joints twice at 4 months and 17 days before her visual symptom. Visual acuity was 20/50 in the right and 20/40 in the left eyes. Anterior segment examination was significant for mild-to-moderate nuclear sclerosis in both eyes. Fundus examination revealed multiple bilateral small to intermediate drusen in the temporal macula and along vascular arcades. A large serous PED of 4-disc diameter in size without hemorrhage was found in the right macula [Figure 1]. There appeared to be an adjacent small serous PED at the inferotemporal aspect of the large serous PED which coalesced into a single large serous PED during follow-up. Optical coherence tomography (OCT) (Spectralis®; Heidelberg, Germany) confirmed the presence of the large serous PED with a small pocket of SRF at the apex of the serous PED. Enhanced-depth imaging-OCT revealed dilated outer choroidal vessels with attenuation of inner choroid beneath the serous PED. Subfoveal choroidal thickness was 322 μm.\n\nFigure 1 Multimodal imaging of the right eye at the first presentation. (a) Infrared reflectance and optical coherence tomography (OCT) of the macula and (b) fundus photograph show a large pigment epithelial detachment (PED) at the macula with surrounding small and intermediate drusen. There was a small satellite PED which coalesced into a single large PED 6 days later. (c) Enhanced-depth imaging OCT scan through the foveal center shows a large PED with serous subretinal fluid at its apex\n\nFFA (Spectralis®) showed hyperfluorescence pooling of the serous PED and some leakage into the SRF at the apex of the serous PED [Figure 2]. ICGA (Spectralis®) showed choroidal hyperpermeability surrounding the serous PED without any evidence of choroidal neovascularization (CNV) or polyps seen [Figure 3].\n\nFigure 2 Fluorescein angiography of the right eye shows pooling hyperfluorescence of the pigment epithelial detachment (PED). Hyperfluorescence was more intense at the inferotemporal area and gradually diffused through the residual area of the PED. There was some late dye leakage into subretinal fluid in the area of foveal avascular zone\n\nFigure 3 Indocyanine green angiography (ICGA) of the right eye shows hypocyanescence blockage of the pigment epithelial detachment (PED). There was choroidal hyperpermeability surrounding the PED in the mid to the late phase of the ICGA. No evidence of choroidal neovascularization was identified\n\nThe patient was, however, treated with 1.25 mg of intravitreal bevacizumab injection, but the serous PED and SRF persisted. The treatment was then switched to 2 mg of intravitreal aflibercept injection twice monthly. The serous PED and SRF were dramatically resolved, and her vision improved to 20/30 [Figure 4]. The subfoveal choroidal thickness was 294 μm. Two months after the last aflibercept injection, a shallow serous PED recurred, and the patient was reevaluated. FFA and ICGA did not reveal any signs of CNV or polyps despite the fact that the obscuration by the shallow PED was minimal [Figure 5]. Nevertheless, due to the well responsiveness to aflibercept, the patient was treated again with 2 mg of aflibercept injection which resulted in a complete resolution of the serous PED 1 month later. OCTA (RTVue, Optovue, Fremont, California) was performed at this time when there was no PED, and it confirmed the absence of any abnormal choroidal neovascular membrane [Figure 6].\n\nFigure 4 Evolution of the pigment epithelial detachment (PED) and subretinal fluid (SRF) of the patient. (a) Baseline enhance-depth imaging optical coherence tomography. (b) 1 month after the first intravitreal injection (bevacizumab), the PED was partially resolved, but SRF increased. (c) 1 month after the second injection (aflibercept), partial resolution of both PED and SRF is shown. (d) 1 month after the third injection (aflibercept), both PED and SRF were completely resolved. The patient's visual acuity improved to 20/30\n\nFigure 5 Multimodal imaging of the right eye at the first relapse of the pigment epithelial detachment (PED). (a) Fundus photograph, (b) infrared image, and (c) enhance-depth imaging optical coherence tomography show a relapse of shallow serous PED without subretinal fluid. (d) Fundus fluorescein angiography demonstrates the pooling of the PED beginning at the inferotemporal area. (e) Indocyanine green angiography shows hypocyanescence blockage of the PED. No abnormal hypercyanescence plaque of choroidal neovascularization was identified. The choroidal hyperpermeability was less intense than at the baseline visit\n\nFigure 6 Optical coherence tomography angiography when the pigment epithelial detachment (PED) was completely resolved (2 months after the fourth intravitreal injection). There was no sign of abnormal neovascularization in the choriocapillaris layer in both areas which used to be (a) the large PED and (b) the small satellite PED\n\nThe disease had been in quiescence for 3 months before she reported blurry vision of her right eye again with a history of 8 mg of intravenous dexamethasone injection 7 days before presentation. The visual acuity was 20/40, and OCT showed a recurrence of the large serous PED with shallow SRF on the top [Figure 7]. She was observed for 1 month without improvement and was then treated with intravitreal aflibercept. The PED and SRF again completely disappeared 1 month after the treatment, and her vision was back to 20/25. Four months after the last intravitreal injection, a shallow PED recurred but this time was spontaneously resolved with observation. At the last follow-up visit (22 months after the last intravitreal injection), her vision remained stable, and OCT showed pachychoroid without further recurrences of PED or SRF [Figure 7].\n\nFigure 7 Enhanced-depth imaging optical coherence tomography shows relapses of the (PED). (a) 7 days after receiving 8 mg intravenous dexamethasone, the second relapse of the large PED is shown. (b) After 1 month of observation, subretinal fluid (SRF) developed. (c) After receiving the fifth intravitreal aflibercept injection, PED and SRF completely disappeared. (d) 4 months after the last injection, a shallow PED recurred but was spontaneously resolved. (e) 7 months, (f) 11 months, and (g) 22 months after the last injection, there were no further recurrences of the disease\n\nDISCUSSION\n\nWe reported a unique case of a diagnosis dilemma of neovascular AMD versus a non-neovascular pachychoroid disease. With the clinical presentation of a large serous PED and SRF in a background of macular drusen in an elderly woman, neovascular AMD was high in the differential diagnosis. FFA and ICGA were performed to confirm the diagnosis, but no evidence of Type 1 NV or polyps could be identified. However, on FFA, it might be difficult to identify occult Type 1 NV in the presence of a large serous PED due to obscuration by fluorescein leakage and pooling of the PED itself. On ICGA, with less dye leakage compared with FFA, it could also be difficult to identify a tiny plaque of CNV, especially in the presence of hypocyanescence serous PED. A therapeutic trial with intravitreal anti-VEGF was performed with good clinical response, making the diagnosis of neovascular AMD even more likely. In this patient, on the other hand, there were also clinical characteristics of PDS, namely dilated large Haller's layer vessels (pachyvessels) underlying the serous PED and choroidal hyperpermeability in the mid to the late phase of ICGA, which were not features of typical AMD. Interestingly, after anti-VEGF injections, the serous PED was completely flattened, and no irregularities of the retinal pigment epithelial (RPE) layer suspicious of occult Type 1 NV were identified. FFA and ICGA at this time when there was no obscuration by the serous PED did not reveal any evidence of Type 1 NV or polyps. OCTA also confirmed the absence of any Type 1 NV, leading to the diagnosis of a non-neovascular disease in PDS. The fellow eye also demonstrated dilated large Haller's layer vessels and choroidal hyperpermeability consistent with the pachychoroid phenotype [Figure 8] which is typically bilateral.\n\nFigure 8 Enhanced-depth imaging optical coherence tomography of the fellow eye shows dilated Haller's layer vessels with thinning of the overlying inner choroid at (a) subfoveal area and (b) parafoveal area. Indocyanine green angiography shows dilated large choroidal vessels in (c) early phase and corresponding choroidal hyperpermeability in (d) mid to late phase. The solid line and the dash line in C represent the cross-section levels for A and B, respectively\n\nPDS comprises several diseases that share common features of focal or diffuse choroidal thickening, pachyvessels with attenuation of the inner choroid, and choroidal hyperpermeability.45 The spectrum includes pachychoroid pigment epitheliopathy, CSC, pachychoroid neovasculopathy, polypoidal choroidal vasculopathy, focal choroidal excavation, and peripapillary pachychoroid syndrome. A case of relapsing PED without SRF in pachychoroid pigment epitheliopathy has been described.6 Our patient was, however, most likely compatible with CSC but with atypical presentation of serous PED more prominent than SRF. The choroidal hyperpermeability and extravascular hydrostatic pressure may cause accumulation of fluid under the RPE, resulting in serous PED and SRF. Interestingly, our patient showed that the choroidal hyperpermeability on ICGA was reduced when the serous PED was flattened as compared with baseline [Figures 3 and 5], supporting its role in the disease pathogenesis. The reason why the serous PED was more prominent than SRF in this patient compared with typical CSC is unknown, but it may depend on varying RPE-Bruch's membrane adhesion force between individual patients.78 The association between steroid and recurrence of serous PED in this patient was apparent and also supported the diagnosis of CSC, for which steroid is a well-known risk factor.\n\nOur patient responded very well to aflibercept with regard to recurrences of the serous PED. Growing evidence has shown that PDS could be responsive to anti-VEGF in some cases,910111213 and aflibercept showed more efficacy than ranibizumab.7 Aflibercept may reduce choroidal hyperpermeability in PDS and was shown to cause reduction of choroidal thickness in pachychoroid neovasculopathy.91415 Further studies are still needed to assess the efficacy and long-term safety of anti-VEGF against PDS.\n\nThere is a small risk of RPE tear after anti-VEGF injection in cases of neovascular PED, especially when the PED is very high. The RPE tear can occur because of the contraction of the neovascular component under the PED itself, which is potentially induced by anti-VEGF injection.16 However, in cases of large non-neovascular PED similar to the patient, whether the anti-VEGF would increase the risk of RPE tear is still unknown, and there are currently no standard treatments for this condition. On the other hand, it is known that anti-VEGF can decrease vascular permeability and may help to flatten the serous PED, as seen in this patient. However, larger studies are needed to validate the use of anti-VEGF in this specific condition.\n\nIn summary, this patient demonstrated a large relapsing serous PED with small SRF in non-neovascular PDS (likely CSC). The relapsing serous PED was associated with steroid use, could resolve spontaneously, and also responded very well to aflibercept. This clinical presentation in elderly patients with macular drusen could be confused with neovascular AMD. The choroidal thickness might look normal due to aging and the co-existence of dry AMD. Multimodal retinal imaging was crucial to reveal other clinical features of PDS in order to guide correct diagnosis and management.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 Phasukkijwatana N Freund KB Dolz-Marco R Al-Sheikh M Keane PA Egan CA Peripapillary pachychoroid syndrome Retina 2018 38 1652 67 29135799\n2 Dansingani KK Balaratnasingam C Klufas MA Sarraf D Freund KB Optical coherence tomography angiography of shallow irregular pigment epithelial detachments in pachychoroid spectrum disease Am J Ophthalmol 2015 160 1243 5400 26319161\n3 Pang CE Freund KB Pachychoroid neovasculopathy Retina 2015 35 1 9 25158945\n4 Warrow DJ Hoang QV Freund KB Pachychoroid pigment epitheliopathy Retina 2013 33 1659 72 23751942\n5 Akkaya S Spectrum of pachychoroid diseases Int Ophthalmol 2018 38 2239 46 28766279\n6 Zhang F Qiu Y Stewart JM A case of relapsing retinal pigment epithelial detachment in peripapillary pachychoroid pigment epitheliopathy Retin Cases Brief Rep 2018 12 Suppl 1 S110 13 29135703\n7 Bird AC Marshall J Retinal pigment epithelial detachments in the elderly Trans Ophthalmol Soc U K 1986 105 (Pt 6) 674 82 3310342\n8 Hussain AA Starita C Hodgetts A Marshall J Macromolecular diffusion characteristics of ageing human Bruch's membrane: Implications for age-related macular degeneration (AMD) Exp Eye Res 2010 90 703 10 20206163\n9 Jung BJ Kim JY Lee JH Baek J Lee K Lee WK Intravitreal aflibercept and ranibizumab for pachychoroid neovasculopathy Sci Rep 2019 9 2055 30765771\n10 Okamoto M Matsuura T Ogata N Choroidal thickness and choroidal blood flow after intravitreal bevacizumab injection in eyes with central serous chorioretinopathy Ophthalmic Surg Lasers Imaging Retina 2015 46 25 32 25559505\n11 Kim DY Joe SG Yang HS Lee JY Kim JG Yoon YH Subfoveal choroidal thickness changes in treated idiopathic central serous chorioretinopathy and their association with recurrence Retina 2015 35 1867 74 25946693\n12 Pitcher JD 3rd Witkin AJ DeCroos FC Ho AC A prospective pilot study of intravitreal aflibercept for the treatment of chronic central serous chorioretinopathy: The CONTAIN study Br J Ophthalmol 2015 99 848 52 25595177\n13 Lim SJ Roh MI Kwon OW Intravitreal bevacizumab injection for central serous chorioretinopathy Retina 2010 30 100 6 20010322\n14 Hata M Oishi A Tsujikawa A Yamashiro K Miyake M Ooto S Efficacy of intravitreal injection of aflibercept in neovascular age-related macular degeneration with or without choroidal vascular hyperpermeability Invest Ophthalmol Vis Sci 2014 55 7874 80 25395483\n15 Koizumi H Kano M Yamamoto A Saito M Maruko I Kawasaki R Short-term changes in choroidal thickness after aflibercept therapy for neovascular age-related macular degeneration Am J Ophthalmol 2015 159 627 33 25555799\n16 Nagiel A Freund KB Spaide RF Munch IC Larsen M Sarraf D Mechanism of retinal pigment epithelium tear formation following intravitreal anti-vascular endothelial growth factor therapy revealed by spectral-domain optical coherence tomography Am J Ophthalmol 2013 156 981 800 23972309\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2452-2325",
"issue": "33(1)",
"journal": "Journal of current ophthalmology",
"keywords": "Age-related macular degeneration; Anti-vascular endothelial growth factors; Central serous chorioretinopathy; Pachychoroid; Pigment epithelial detachment",
"medline_ta": "J Curr Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101678509",
"other_id": null,
"pages": "82-87",
"pmc": null,
"pmid": "34084962",
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"publication_types": "D002363:Case Reports",
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"title": "Non-Neovascular Pachychoroid Disease Mimicking Exudative Age-Related Macular Degeneration.",
"title_normalized": "non neovascular pachychoroid disease mimicking exudative age related macular degeneration"
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"abstract": "Acquired estrogen receptor gene (ESR1) mutations have been recently reported as a marker of resistance to aromatase inhibitors in hormone receptor positive metastatic breast cancer. We retrospectively considered seven patients treated for metastatic breast cancer with available samples from the primary tumor before any treatment, cryopreserved metastasis removed during progression and concomitant plasmas. All these seven patients were in disease progression after previous exposure to aromatase inhibitors for at least 6 months, and were assessed for ESR1 mutations detection in tumor and circulating DNA. For these patients, Sanger sequencing identified four metastases with clear ESR1 mutation and one possible, whereas digital PCR identified six mutated metastases. Then, under blind conditions and using digital PCR, corresponding circulating ESR1 mutations were successfully detected in four of these six metastatic breast cancer patients. Moreover, in two patients with serial blood samples following treatments exposure, the monitoring of circulating ESR1 mutations clearly predicted disease evolution. In the context of high interest for ESR1 mutations, our results highlight that these acquired recurrent mutations may be tracked in circulating tumor DNA and may be of clinical relevance for metastatic breast cancer patient monitoring.",
"affiliations": "INSERM U1079, Rouen, France.;Equipe De Recherche En Oncologie (IRON), Rouen University Hospital and Centre Henri Becquerel, Rouen, France.;INSERM U1079, Rouen, France.;Equipe De Recherche En Oncologie (IRON), Rouen University Hospital and Centre Henri Becquerel, Rouen, France.;Department of Surgery, Clinique Du Cèdre, Bois-Guillaume, France.;Department of Bio-Pathology, Centre Henri Becquerel, Rouen, France.;INSERM U1079, Rouen, France.;Department of Bio-Pathology, Centre Henri Becquerel, Rouen, France.;INSERM U918, Centre Henri Becquerel, Rouen, France.;Department of Medical Oncology, Centre Henri Becquerel, Rouen, France.;Department of Medical Oncology, Centre Henri Becquerel, Rouen, France.;Department of Medical Oncology, Centre Henri Becquerel, Rouen, France.;Equipe De Recherche En Oncologie (IRON), Rouen University Hospital and Centre Henri Becquerel, Rouen, France.;Department of Medical Oncology, Centre Henri Becquerel, Rouen, France.;Department of Medical Oncology, Centre Henri Becquerel, Rouen, France.;Department of Medical Oncology, Centre Henri Becquerel, Rouen, France.;Department of Medical Oncology, Centre Henri Becquerel, Rouen, France.;INSERM U1079, Rouen, France.;INSERM U1079, Rouen, France.;Equipe De Recherche En Oncologie (IRON), Rouen University Hospital and Centre Henri Becquerel, Rouen, France.",
"authors": "Sefrioui|David|D|;Perdrix|Anne|A|;Sarafan-Vasseur|Nasrin|N|;Dolfus|Claire|C|;Dujon|Antoine|A|;Picquenot|Jean-Michel|JM|;Delacour|Julien|J|;Cornic|Marie|M|;Bohers|Elodie|E|;Leheurteur|Marianne|M|;Rigal|Olivier|O|;Tennevet|Isabelle|I|;Thery|Jean-Christophe|JC|;Alexandru|Cristina|C|;Guillemet|Cécile|C|;Moldovan|Cristian|C|;Veyret|Corinne|C|;Frebourg|Thierry|T|;Di Fiore|Frédéric|F|;Clatot|Florian|F|",
"chemical_list": "D047072:Aromatase Inhibitors; D004273:DNA, Neoplasm; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha",
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"journal": "International journal of cancer",
"keywords": "ESR1 mutations; aromatase inhibitor resistance; circulating tumor DNA; digital PCR; metastatic breast cancer",
"medline_ta": "Int J Cancer",
"mesh_terms": "D047072:Aromatase Inhibitors; D001943:Breast Neoplasms; D004273:DNA, Neoplasm; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha; D005260:Female; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies",
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"references": null,
"title": "Short report: Monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer.",
"title_normalized": "short report monitoring esr1 mutations by circulating tumor dna in aromatase inhibitor resistant metastatic breast cancer"
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"abstract": "Palmoplantar psoriasis is a chronic debilitating type of psoriasis. Treatment options for this disease are poorly studied. This chart review evaluated the use of methotrexate alone and in combination with 7 other systemic therapies in 48 patients with palmoplantar psoriasis. The findings demonstrate that methotrexate is a relatively well-tolerated and effective treatment for palmoplantar psoriasis, amenable as either monotherapy or in combination with other systemic agents.",
"affiliations": null,
"authors": "Wald|Jenna M|JM|;Klufas|Daniel M|DM|;Strober|Bruce E|BE|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D003879:Dermatologic Agents; D007166:Immunosuppressive Agents; D013792:Thalidomide; D016572:Cyclosporine; D000069285:Infliximab; D000069549:Ustekinumab; D000068879:Adalimumab; D009173:Mycophenolic Acid; D000068800:Etanercept; C505730:apremilast; D008727:Methotrexate",
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"mesh_terms": "D000068879:Adalimumab; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016572:Cyclosporine; D003879:Dermatologic Agents; D004359:Drug Therapy, Combination; D000068800:Etanercept; D005260:Female; D005533:Foot Dermatoses; D006229:Hand Dermatoses; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009173:Mycophenolic Acid; D011565:Psoriasis; D012720:Severity of Illness Index; D013792:Thalidomide; D000069549:Ustekinumab; D055815:Young Adult",
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"title": "The Use of Methotrexate, Alone or in Combination With Other Therapies, for the Treatment of Palmoplantar Psoriasis.",
"title_normalized": "the use of methotrexate alone or in combination with other therapies for the treatment of palmoplantar psoriasis"
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"abstract": "BACKGROUND\nAdvanced therapy-refractory parotid gland carcinomas have a poor prognosis with limited therapy options. We used molecular profiling to offer molecular guided therapies to patients with advanced metastatic parotid gland malignancies.\n\n\nMETHODS\nIn this retrospective analysis we describe the molecular profiling of ten patients diagnosed with therapy-refractory metastatic parotid gland malignancies.\n\n\nRESULTS\nWe identified seven genetic aberrations in five patients: two mutations in CDKN2A and one mutation in APC, ATM, TP53, SMARCB1 and FGFR1, respectively. No mutations were detected in five patients. The IHC demonstrated frequent expressions of EGFR and p‑mTOR, as well as PTEN in eight patients. For four fifths (n = 8) of the patients, a targeted therapy was suggested. Eventually, three patients received the targeted therapy recommendation and one patient achieved stable disease for 14 months.\n\n\nCONCLUSIONS\nA total of eight therapy recommendations were provided. Based on our observations, molecular-guided therapies may be a feasible treatment approach for this rare disease entity.",
"affiliations": "Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.;Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria.;Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.;Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.;Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria. gerald.prager@meduniwien.ac.at.",
"authors": "Taghizadeh|Hossein|H|http://orcid.org/0000-0002-0927-6498;Müllauer|Leonhard|L|;Mader|Robert M|RM|;Füreder|Thorsten|T|;Prager|Gerald W|GW|",
"chemical_list": null,
"country": "Austria",
"delete": false,
"doi": "10.1007/s00508-020-01778-8",
"fulltext": "\n==== Front\nWien Klin Wochenschr\nWien Klin Wochenschr\nWiener Klinische Wochenschrift\n0043-5325 1613-7671 Springer Vienna Vienna \n\n33296026\n1778\n10.1007/s00508-020-01778-8\nOriginal Article\nMolecularly guided treatment of metastatic parotid gland carcinoma in adults\nhttp://orcid.org/0000-0002-0927-6498Taghizadeh Hossein MD12 Müllauer Leonhard MD, PhD3 Mader Robert M. PhD1 Füreder Thorsten MD12 Prager Gerald W. MDgerald.prager@meduniwien.ac.at 12 1 grid.22937.3d0000 0000 9259 8492Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria \n2 Comprehensive Cancer Center Vienna, Vienna, Austria \n3 grid.22937.3d0000 0000 9259 8492Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria \n9 12 2020 \n9 12 2020 \n2021 \n133 1 32 40\n5 4 2020 16 11 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Summary\nBackground\nAdvanced therapy-refractory parotid gland carcinomas have a poor prognosis with limited therapy options. We used molecular profiling to offer molecular guided therapies to patients with advanced metastatic parotid gland malignancies.\n\nMethods\nIn this retrospective analysis we describe the molecular profiling of ten patients diagnosed with therapy-refractory metastatic parotid gland malignancies.\n\nResults\nWe identified seven genetic aberrations in five patients: two mutations in CDKN2A and one mutation in APC, ATM, TP53, SMARCB1 and FGFR1, respectively. No mutations were detected in five patients. The IHC demonstrated frequent expressions of EGFR and p‑mTOR, as well as PTEN in eight patients. For four fifths (n = 8) of the patients, a targeted therapy was suggested. Eventually, three patients received the targeted therapy recommendation and one patient achieved stable disease for 14 months.\n\nConclusion\nA total of eight therapy recommendations were provided. Based on our observations, molecular-guided therapies may be a feasible treatment approach for this rare disease entity.\n\nKeywords\nMolecular profilingMolecular guided treatmentPrecision cancer medicineHead and neck cancerMolecular oncologyMedical University of ViennaOpen access funding provided by Medical University of Vienna.\n\nissue-copyright-statement© Springer-Verlag GmbH Austria, part of Springer Nature 2021\n==== Body\nIntroduction\nSalivary gland carcinomas (SGC) comprise rare heterogeneous malignancies that account for only 5% of all head and neck cancers. The SGCs are classified into 24 subtypes according to the World Health Organization (WHO) definition. Likewise, the tumor biology and prognosis of SGCs markedly differ between histological types [1–4]. Among these glands, most malignancies occur in the parotid gland. The parotid gland carcinoma (PGC) is a relatively rare cancer, making up only 0.3% of all cancers combined [5]. The PGC with distant metastases, mainly in the lungs and bones, has a dismal median survival prognosis of 7.3 months despite therapeutic efforts [6].\n\nThe mainstay of treatment is complete surgical resection followed by postoperative radiotherapy (depending on the subtype and risk features). In surgical interventions, complete excision of the PGC is carried out with preservation of the functioning facial nerve, provided there is no tumor invasion. Systemic chemotherapy is generally indicated for patients with recurrent and/or metastatic PGC [5, 7–9].\n\nThe most common histological subtype in primary PGC is mucoepidermoid carcinoma (MEC) [10, 11]. Given the rarity of this disease, there are, apart from parotidectomy and radiotherapy, few well-established therapy standards for how to treat patients with progressive stage IV PGC [7].\n\nThere has recently been an effort to individualize therapy options in cancer diseases. In some instances, tailored therapy attempts with immunotherapeutics or tyrosine kinase inhibitors are used, e.g., trastuzumab in HER2-positive breast cancer or gastric cancer, imatinib in Philadelphia chromosome-positive chronic myeloid leukemia (Ph + CML), BRAF-directed therapy with vemurafenib or dabrafenib/trametinib in melanoma [12–14].\n\nEmerging novel agents, such as the profiling of tumor molecular alterations and mutations as well as the identification of druggable targets and the ground-breaking pilot trial by von Hoff et al. have ushered in a new era of medicine; this approach has received many titles, such as individualized, stratified, tailored, or precision cancer medicine [15]. The main rationale of PCM is to match a therapeutic agent to its corresponding target for precise tailored therapy fitting a specific patient, aiming to achieve a deep durable and sustainable response without damaging healthy cells and tissues. This matches the tailored “therapeutic dress” to the patient [16].\n\nWe conducted a retrospective subgroup analysis of our precision molecular register, exclusively focusing on patients with progressive PGC with no available standard treatment options. These patients had been enrolled and whose tumors had been profiled in our special PCM platform. We sought to map the molecular profiles of advanced, relapsed and therapy-refractory PGC to evaluate whether there are any aberrations that can be targeted by a tailored therapy.\n\nMaterial and methods\nEthics, consent and permission\nThe study was conducted in accordance with the International Conference on Harmonization E6 requirements for good clinical practice and with the ethical principles outlined in the Declaration of Helsinki. All patients had to provide written informed consent before inclusion in our PCM platform. Furthermore, the institutional ethics committee has also approved this subanalysis (Nr. 1039/2017).\n\nPatients and design of the precision medicine platform\nPatients with PGC who had progressed through all standard treatment options were eligible for inclusion in our platform for precision medicine, provided archival tissue samples were available. Patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Our platform for precision medicine is not a clinical trial, but intends to provide the possibility of a targeted therapy to patients where no active anti-tumor treatment is available.\n\nTissue samples\nFormalin-fixed, paraffin-embedded tissue from patients with advanced PGC that were refractory to all available standard treatment lines were sent to or retrieved from the archive of the Department of Pathology.\n\nCancer gene panel sequencing\nDNA was extracted from paraffin-embedded tissue blocks with a QIAamp Tissue KitTM (Qiagen, Hilden, Germany) and 10 ng DNA per tissue sample was provided for sequencing. The DNA library was created by multiplex polymerase chain reaction with the 161-gene next-generation sequencing panel of Oncomine Comprehensive Assay v3 (Thermo Fisher Scientific, Waltham, MA, USA). The panel includes driver mutations, oncogenes, tumor suppressor genes, and gene fusions. See supplementary information for complete list of the gene panel. The Oncomine Comprehensive Assay v3 was optimized for sequencing on an Ion Personal Genome Machine System (Thermo Fisher Scientific). The generated sequencing data were afterwards analyzed with the help of the Ion Reporter Software (Thermo Scientific Fisher). We referred to BRCA Exchange, ClinVar, COSMIC, dbSNP, OMIM and 1000 genomes for variant calling and classification. The variants were classified according to a five-tier system comprised of the modifiers pathogenic, likely pathogenic, uncertain significance, likely benign, or benign. This classification was based on the standards and guidelines for the interpretation of sequence variants of the American College of Medical Genetics and Genomics. The variants pathogenic and likely pathogenic were taken into consideration for the recommendation of targeted therapy.\n\nImmunohistochemistry\nThe IHC was performed using 2‑μm-thin tissue sections read by a Ventana Benchmark Ultra stainer (Ventana, Tucson, AZ, USA). The following antibodies were applied: anaplastic lymphoma kinase (ALK, clone 1A4; Zytomed, Berlin, Germany), CD20 (clone L26; Dako Omnis from Agilent Technologies, Santa Clara, CA, USA), CD30 (clone BerH2; Agilent Technologies, Vienna, Austria), epidermal growth factor receptor (EGFR, clone 3C6; Ventana), estrogen receptor (clone SP1; Ventana), human epidermal growth factor receptor 2 (HER2, clone 4B5; Ventana), HER3 (clone SP71; Abcam, Cambridge, UK), C‑kit receptor (KIT, clone 9.7; Ventana), MET (clone SP44; Ventana), NTRK (clone EPR17341, Abcam), phosphorylated mammalian target of rapamycin (p-mTOR, clone 49F9; Cell Signaling Technology, Danvers, MA, USA), platelet-derived growth factor alpha (PDGFRA, rabbit polyclonal; Thermo Fisher Scientific), PDGFRB (clone 28E1, Cell Signaling Technology), programmed death-ligand 1 (PD-L1, clone E1L3N; Cell Signaling Technology), progesterone receptor (clone 1E2; Ventana), phosphatase and tensin homolog (PTEN, clone Y184; Abcam) and ROS1 (clone D4D6; Cell Signaling Technology).\n\nTo assess the immunostaining intensity for the antigens EGFR, p-mTOR, PDGFRA, PDGFRB and PTEN, a combinative semiquantitative score for immunohistochemistry was used. The immunostaining intensity was graded from 0 to 3 (0 = negative, 1 = weak, 2 = moderate, 3 = strong). To calculate the score, the intensity grade was multiplied by the percentage of corresponding positive cells: (maximum 300) = (% negative × 0) + (% weak × 1) + (% moderate × 2) + (% strong × 3).\n\nThe immunohistochemical staining intensity for HER2 was scored from 0 to 3+ (0 = negative, 1+ = negative, 2+ = positive, 3+ = positive) pursuant to the scoring guidelines of the Dako HercepTestR from the company Agilent Technologies (Agilent Technologies, Santa Clara, CA, USA). In the case of HER2 2+, a further test with HER2 in situ hybridization was performed to verify amplification of the HER2 gene.\n\nEstrogen receptor and progesterone receptor staining were graded according to the Allred scoring system [17] from 0 to 8 and MET staining was scored from 0 to 3 (0 = negative, 1 = weak, 2 = moderate, 3 = strong).\n\nFor PD-L1, the tumor proportion score was calculated, which is the percentage of viable malignant cells showing membrane staining.\n\nStaining for ALK, CD30, CD20 and ROS1 was classified as positive or negative based on the percentage of reactive tumor cells but without graduation of the staining intensity. In ALK or ROS1 positive cases, the presence of a possible gene translocation was evaluated by fluorescence in situ hybridization (FISH).\n\nAll antibodies used in this study were validated and approved at the clinical institute of pathology and are used in routine IHC staining for clinical purposes. The antibodies have been validated, by proper positive and negative tissue controls and by non-IHC methods, such as immunoblotting and flow cytometry, to detect the respective epitope of the antigens. For the control, the use of the antibodies was optimized in terms of intensity, concentration, signal/noise ratio, incubation times and blocking. The negative control was conducted by omitting the primary antibody and by substitution of isotype-specific antibody and serum at the exact same dilution and laboratory conditions as the primary antibody to preclude unspecific binding.\n\nFor the positive control, the antibodies were shown not to cross-react with closely related molecules of the target epitope.\n\nFluorescence in situ hybridization\nThe FISH was performed with 4‑μm-thick formalin-fixed, paraffin-embedded tissue sections. The following FISH probes were employed: ALK (2p23.1; Abbott, Abbott Park, IL, USA), RET (10q11; Kreatech, Berlin, Germany), PTEN (10q23.31)/centromere 10, and ROS1 (ZytoVision, Bremerhaven, Germany), 200 cell nuclei per tumor were evaluated. The cut-off level for an aberrant ALK, RET, and ROS1 FISH was ≥15% of cells with a split-apart signal. The PTEN FISH was considered positive for PTEN gene loss with ≥30% of cells with only one or no PTEN signals. A chromosome 10 centromere FISH probe served as a control for ploidy of chromosome 10.\n\nMultidisciplinary boards (molecular tumor boards for PCM)\nAfter thorough examination of the molecular profile of each tumor sample by a qualified and competent molecular pathologist, the results and findings were reviewed in multidisciplinary tumor boards (MTB) that were held every other week. Members of the board included molecular pathologists, radiologists, clinical oncologists, biostatisticians, and basic scientists. The MTB recommended the targeted therapy based on the specific molecular profile of each patient. The targeted therapies included tyrosine kinase inhibitors, checkpoint inhibitors (e.g. anti-PD-L1 monoclonal antibodies), and growth factor receptor antibodies with or without endocrine therapy. The treatment recommendations by the MTB were prioritized depending on the level of evidence from high to low according to phase III to phase I trials.\n\nIf more than one druggable molecular aberration was identified, the MTB recommended a therapy regimen to target as many molecular aberrations as possible, with special consideration given to the toxicity profile of each antitumor agent and their potential interactions. Since all patients were given all available standard treatment options for their cancer disease prior to their inclusion in our PCM platform, nearly all targeted agents were suggested as off-label use. If the tumor profile and the clinical characteristics of a patient met the requirements of a clinical trial for targeted therapies that was conducted in our cancer center, patients were preferentially asked if they wanted to participate in this trial.\n\nDescriptive statistics\nFor data description, we used measures of central tendency including the mean and median. We also used the method of frequency distribution to delineate the characteristics of the PGC patients.\n\nResults\nAll ten patients diagnosed with progressive primary PGC were included in this analysis from our platform for precision medicine that has so far profiled over 600 patients with various advanced solid tumors. All PGC patients were Europeans. Five men and five women were diagnosed with five different histological subtypes of primary PGC. The subtypes were acinic cell carcinoma (n = 1), adenocarcinoma NOS (n = 3), adenoid cystic carcinoma (n = 3), carcinoma ex pleomorphic adenoma (n = 1), and primary squamous cell carcinoma (n = 2). The primary tumor location was the right side in six patients (60%) and the left side in four patients (40%).\n\nAt the time of molecular profiling, all patients had an advanced, therapy-refractory and relapsed PGC in stage IV with distant metastases, mainly in the bones and lungs. The whole cohort had undergone parotidectomy and radiation therapy. Four patients had also received prior chemotherapy: two patients were treated with carboplatin and paclitaxel, one patient received cisplatin and cetuximab, and another patient was given a CAP regimen consisting of cyclophosphamid, doxorubicin (trade name Adriamycin) and a platinum-based agent (usually cisplatin).\n\nThe median age at the time of initial diagnosis was 59.5 years, ranging from 27 to 82 years, and the median age at the time of molecular profiling was 63 years, ranging from 37 to 83 years (Table 1).Table 1 Patient characteristics (N = 10)\n\nPatient characteristics\tNumber\t\nMedian age at first diagnosis (years)\t59.5\t\nMedian age at molecular profiling (years)\t63\t\nMen\t5\t\nWomen\t5\t\nHistological subtypes of parotid gland carcinoma\t5\t\nCaucasian\t10\t\nRelapsed disease\t10\t\nStage IV\t10\t\nParotid gland carcinoma on the right side\t6\t\nParotid gland carcinoma on the left side\t4\t\nTherapy recommendations\t8\t\n\n\nOf the ten tissue samples, five were from metastatic sites and five from the primary site.\n\nIn total, we identified seven molecular aberrations in five patients: two mutations in CDKN2A and one mutation in each of APC, ATM, TP53, SMARCB1, and FGFR1. No mutations were detected in five patients.\n\nExpression of EGFR, p-mTOR and PTEN was detected by IHC in eight patients. The EGFR median score was 120, and 3 patients had a high EGFR score of between 200 and 300. The expression of p-mTOR was lower with a median score of 70, and 2 patients had a high p-mTOR score of between 200 and 300. Expression of MET and PDGFRA was detectable in six and five samples, respectively. MET expression was weak in four patients and moderate in one patient. One sample exhibited a strong MET expression. Less common expressions were observed for KIT and AR which were observed in three and two patients, respectively. The KIT expression was found to be weak in two samples and moderate in one sample, AR was moderately expressed in both patients with adenocarcinoma.\n\nIHC and FISH were not performed in one patient due to insufficient tumor material.\n\nFor eight of the ten patients, a targeted therapy was suggested based on their individual molecular profile (Table 1). Androgen deprivation therapy (ADT), crizotinib, and cetuximab each were offered in two cases and imatinib and sunitinib were proposed in one case. We refer here to Tables 2 and 3 for the rationale of the therapy suggestions.Table 2 Rational for therapy recommendations\n\nTherapeutic agent (trade name)\tTargets\tOverview of current FDA approval in different entities\tOverview of current EMA approval in different entities\t\nCetuximab (Erbitux)\n\n(n = 2)\n\n\tEGFR\tCRC, HNSCC\tCRC, HNSCC\t\nCrizotinib (Xalkori)\n\n(n = 2)\n\n\tALK, ROS1\n\nMET overexpression\n\n\tALK or ROS1 positive NSCLC\tALK or ROS1 positive NSCLC\t\nImatinib (Gleevec)\n\n(n = 1)\n\n\tPDGFR, KIT, Bcr/Abl\tPh + CML, KIT + GIST, MDS/MPD associated with PDGFR, Ph + ALL\tPh + CML, KIT+ GIST, MDS/MPD associated with PDGFR, Ph + ALL\t\nSunitinib (Sutent)\n\n(n = 1)\n\n\tPDGFR, KIT, VEGFR, RET, FLT3\tRCC, PDAC, GIST\tRCC, PDAC, GIST\t\nABL Abelson murine leukemia viral oncogene homolog 1, ALK Anaplastic lymphoma kinase, ALL acute lymphatic leukemia, BCR breakpoint cluster region, CML chronic myleloid leukemia, CRC colorectal cancer, EGFR epidermal growth factor receptor, EMA European Medicines Agency, FDA Food and Drug Administration, FLT3 fms like tyrosine kinase 3, GIST gastrointestinal stromal tumor, HNSCC Head and neck squamous cell carcinoma, MDS/MPD myelodysplastic syndrome/ myeloproliferative disorder, NSCLC Non-small cell lung carcinoma, PDAC pancreatic ductal adenocarcinoma, PDGFR platelet derived growth factor receptor, Ph+ Philadelphia chromosome positive, p‑mTOR phosphorylated mammalian target of rapamycin, RCC renal cell carcinoma, RET rearranged during transfection, TP53 tumor protein 53, VEGFR vascular endothelial growth factor\n\nTable 3 Detailed characteristics of the PGC patients (n = 10)\n\nPatient number, gender and age\tHistological subtype and\tStage and side\tSite of metastasis\tTissue tested\tDetected mutations by NGS\tIHC\tTherapy recommendation\t\n1\n\nFemale\n\n61 years\n\n\tAcinic cell carcinoma\tIV°\n\nRight\n\n\tLung\tMetastatic\tNo mutation detected\tNot done (due to insufficient tissue material)\tNo recommendation\t\n2\n\nMale\n\n83 years\n\n\tAdenocarcinoma\tIV°\n\nRight\n\n\tLiver lung\tMetastatic\n\n(liver)\n\n\tNo mutation detected\tEGFR 2+,\n\nMET 1+,\n\nPDGFRA 1+,\n\nPTEN 1+,\n\np‑mTOR 3+,\n\nAR 2+\n\n\tAndrogen deprivation therapy\t\n3\n\nFemale\n\n37 years\n\n\tAdenocarcinoma\tIV°\n\nRight\n\n\tBone\tMetastatic\tNo mutation detected\tEGFR 2+,\n\nKIT 2+,\n\nPTEN 2+,\n\np‑mTOR 3+\n\n\tNo recommendation\t\n4\n\nMale\n\n71 years\n\n\tAdenocarcinoma\tIV°\n\nLeft\n\n\tBone\tPrimary\tNo mutation detected\tEGFR 3+,\n\nPTEN 1+,\n\np‑mTOR 1+,\n\nAR 2+\n\n\tAndrogen deprivation therapy\t\n5\n\nMale\n\n46 years\n\n\tAdenoid cystic carcinoma\tIV°\n\nLeft\n\n\tLung\tMetastatic\tNo mutation detected\tKIT 1+,\n\nMET 3+,\n\nPDGFR 1+,\n\nPTEN 1+,\n\np‑mTOR 2+\n\n\tCrizotinib\t\n6\n\nFemale\n\n56 years\n\n\tAdenoid cystic carcinoma\tIV°\n\nRight\n\n\tLung\tPrimary\tATM: exon 32\n\nc.C9142G (p.Leu3048Val)\n\n\tEGFR 3+,\n\nMET 1+,\n\np‑mTOR 1+,\n\nPTEN 1+\n\n\tCetuximab\t\n7\n\nMale\n\n47 years\n\n\tAdenoid cystic carcinoma\tIV°\n\nRight\n\n\tLung\tPrimary\tAPC: exon 16\n\nc.T3920A (p.I1307K)\n\n\tKIT 1+,\n\nEGFR 2+,\n\nMET 1+,\n\nPDGFRA 1+,\n\nPTEN 1+,\n\np‑mTOR 1+\n\n\tImatinib\t\n8\n\nMale\n\n65 years\n\n\tCarcinoma ex pleomorphic adenoma\tIV°\n\nRight\n\n\tLung,\n\nBrain\n\n\tMetastatic\n\n(lung)\n\n\tTP53 (exon 7):\n\nc.C742T\n\n(p.R248W)\n\n\tEGFR 1+,\n\nMET 1+,\n\nPDGFRA 2+,\n\nPTEN 1+,\n\np‑mTOR 1+\n\n\tSunitinib\t\n9\n\nFemale\n\n67 years\n\n\tPrimary squamous cell carcinoma\tIV°\n\nLeft\n\n\tBone,\n\nlung\n\n\tPrimary\tCDKN2A (exon 2): c.151_155delGTCT (p.V51 fs);\n\nFGFR1 (exon 5):\n\nc.478_480delGAT (p.Asp.160del);\n\nSMARCB1 (exon 9):\n\nc.G1130A (p.R3677H)\n\n\tEGFR 3+,\n\nPTEN 2+\n\n\tCetuximab\t\n10\n\nFemale\n\n72 years\n\n\tPrimary squamous cell carcinoma\tIV°\n\nLeft\n\n\tLung\tPrimary\tCDKN2A (exon 2):\n\nc.C341T,\n\n(p.P114L)\n\n\tEGFR 1+,\n\nMET 3+,\n\nPDGFRA 1+,\n\np‑mTOR 1+\n\n\tCrizotinib\t\nValues in parentheses indicate the immunohistochemical score that was calculated as mentioned in the “Materials and methods” section\n\nAPC adenomatous polyposis coli, AR androgen receptor, CDKN2A cyclin-dependent kinase inhibitor 2A, EGFR epidermal growth factor receptor, FiSH fluorescence in situ hybridization, PDGFR platelet derived growth factor receptor, p‑mTOR phosphorylated mammalian target of rapamycin, PTEN phosphatase and tensin homolog, TP53 tumor protein 53, IHC immunohistochemistry, NGS next-generation sequencing\n\n\n\nThe median turnaround time from the initiation of molecular profiling to therapy initiation was 43 days.\n\nEventually, three patients received the targeted therapy. One male patient with an adenocarcinoma was administered bicalutamide as ADT but died because of disease progression before restaging was performed. The second patient with a carcinoma ex pleomorphic adenoma received sunitinib 50 mg orally once daily combined with docetaxel every third week but did not respond to this therapy regimen and experienced progressive disease. The third patient had an adenoid cystic carcinoma and was given imatinib 400 mg orally once daily. He achieved a stable disease for 14 months and tolerated the therapy without any treatment-related adverse events.\n\nDiscussion\nTo our knowledge, this is the first study of individual genomic alterations that have been translated into concrete tailored therapy recommendations in a group of patients with exclusively recurrent, progressive, and therapy-refractory PGC in stage IV in a real-world setting. None of these patients had the histological subtype mucoepidermoid carcinoma (MEC); instead, they had rarer subtypes, making this subgroup analysis even more valuable and unique.\n\nIn this retrospective single center subgroup analysis, we exclusively present the molecular profile of all ten patients with PGC. Their disease was relapsed, therapy-refractory and advanced. Tumor tissue was obtained from all patients and characterized regarding molecular profiles. Subsequently, the genomic information of the patients was discussed in a multidisciplinary tumor board (MTB) for PCM to evaluate the possibility of a genomic-based therapy concept that is independent of the tumor’s histological classification (tissue-agnostic drugs).\n\nTumor samples harbored mutations in APC, ATM, CDKN2A, FGFR1, SMARCB1, and TP53. The IHC revealed expressions of EGFR and p-mTOR as well as PTEN in eight patients.\n\nTherapeutic options recommended were ADT, cetuximab, crizotinib, sunitinib, and imatinib. Two patients with AR expression were offered ADT to control the disease. Two patients with strong MET expression were suggested crizotinib as a tailored therapy. For two patients with high EGFR expression cetuximab was recommended. Imatinib was considered in one patient due to expression of KIT and PDGFRA. Sunitinib was proposed to one patient because of PDGFRA overexpression. A treatment recommendation was derived for eight patients from the MTB. The drugs were carefully selected for an individualized treatment with special respect to the patient’s clinical and treatment history and concomitant therapies and comorbidities. Interestingly, all these recommendations were based on the protein expressions obtained by immunohistochemistry. Thus, our analysis underscores the clinical relevance of immunohistochemistry in precision medicine.\n\nEventually, three patients received the targeted therapy. One patient died before restaging was performed. The second patient received sunitinib and did not respond. Imatinib was applied to the third patient who experienced a stable disease for 14 months. Although this analysis showed that PCM is implementable in daily clinical routine, only one patient had a clinical benefit from this therapy approach. One reason may be the turnaround time: a shorter turnaround time may help to start the targeted therapy earlier and to control the cancer disease. Liquid biopsy may be a viable option to reduce the turnaround time, to monitor the disease and to assess the therapy response. Another reason may be the complexity of PGC. The major challenge is the extreme and complex phenotypical, morphological, histological, clinical, and even intertumor and intratumor heterogeneity within the same tumor tissue [45]. The WHO classification of salivary gland tumors 2017 distinguishes over 20 types of malignant salivary gland tumors [4].\n\nThe heterogeneity, diversity and the multitude of biological differences between patients may urge the development of novel drugs that are capable of targeting various alterations to increase the efficacy of therapeutic agents and to minimize the risk of drug resistance.\n\nThe observed genomic aberrations and overexpression of AR, KIT, and EGFR, PTEN, p-mTOR, and PDGFRA in PGC in this analysis are in keeping with previous studies [18–33]. The rationale for the therapy recommendation with ADT was corroborated by a study by Boon et al. They studied the application of ADT in 35 patients with androgen receptor-positive advanced salivary duct carcinoma, which lead to a median overall survival (OS) of 17 months versus 5 months in 43 patients receiving best supportive care [34].\n\nThe overexpression of MET was seen in all three patients with adenoid cystic carcinoma and is in line with other studies [35]; however, to our knowledge, this is the first report of an overexpression also in carcinoma ex pleomorphic adenoma and primary squamous cell carcinoma. Crizotinib was offered as a molecularly driven treatment approach. Its clinical efficacy in salivary gland cancers has not yet been described in clinical trials.\n\nOnly one study has used molecular profiling to offer an individualized therapy in patients with metastatic salivary gland adenoid cystic carcinoma (ACC). They enrolled a limited 14 patients, of whom 11 actually received the recommended treatment. The investigators reported the clinical benefit of molecularly guided treatment [36]. Imatinib and sunitinib are tyrosine kinase inhibitors that were offered, each in one case, as an alternative therapy in the case of overexpression in PDGFRA/B or KIT. The data pertaining to the use of imatinib in salivary gland cancer are contradictory and unclear. According to two phase II trials that applied imatinib in patients with KIT-positive adenoid cystic cancers of salivary glands, imatinib was not of significant clinical benefit and the best observed response was a stable disease (SD).\n\nAs a limitation, however, it should be noted that only ACC was studied, and PDGFR expression of the tumor tissue was not evaluated [37, 38]. In contrast, another phase II trial tested imatinib in 15 patients with ACC of salivary glands and concluded that imatinib was of clinical benefit because it achieved a partial response (PR) in two patients and a SD in five other patients [39]. Likewise, in another study, imatinib achieved significant regression of initially unresectable ACC of salivary glands in two patients, making them eligible for a salvage resection [40].\n\nSimilar to imatinib, sunitinib was also tested in a phase II trial in 13 patients with ACC of salivary glands and 11 of these achieved stable disease; however, the investigators did not test the patients’ tumors for KIT or PDGFR expression [41]. Dasatinib is another tyrosine kinase inhibitor that was investigated in a phase II trial for patients with recurrent or metastatic KIT expressing ACC and for nonadenoid cystic malignant salivary tumors. It achieved only one PR in a patient with ACC and the experimental treatment demonstrated no activity in non-ACC salivary gland cancer [42].\n\nIn another phase II trial, axitinib was applied in 33 patients with unresectable ACC. Ho et al. reported that axitinib achieved a PR in 3 patients and a SD in 25 patients. The median progression-free survival (PFS) was 5.7 months [43]. Overexpression of EGFR was often observed in salivary gland cancers and provides a solid and sound rationale for the administration of cetuximab [26, 27]. Its clinical efficacy was examined by Locati et al. in 2009 in salivary gland carcinomas, and they reported a clinical benefit rate of 50% [44].\n\nNotably, we identified p-mTOR overexpression in eight patients; however, we did not consider p-mTOR inhibition with everolimus because of the low evidence for clinical efficacy.\n\nDespite great research efforts and the investigated agents in PGC and other salivary gland cancers, progressive recurrent PGC has a dismal prognosis, and because of the rarity of the disease, well-established therapeutic options are scarce.\n\nGreat strides in the in-depth analysis of the vast genetic and epigenetic landscape of salivary gland cancers have been made in recent years; however, the PCM approach remains in its infancy when it comes to implementing novel individualized therapeutic strategies and concepts for this malignancy [33, 45, 46].\n\nIt is challenging to classify and prioritize the plethora of reported genetic alterations and epigenetic changes to identify actionable targets and to choose adequate tailored therapeutic measures. Thus, the roles of most identified alterations are undefined regarding pathogenesis, therapeutic consequences, and implications [47].\n\nAnother major challenge is the extreme and complex phenotypical, morphological, histological, clinical, and even intertumor and intratumor heterogeneity within the same tumor tissue [45]. The WHO classification of salivary gland tumors 2017 distinguished over 20 types of malignant salivary gland tumors [4]. The heterogeneity, diversity and the multitude of biological differences between patients may urge the development of novel drugs that are capable of targeting various alterations to increase the efficacy of therapeutic agents and to minimize the risk of drug resistance. In light of the complexity of PGC, molecularly driven clinical trials in PCM have to be designed as basket and umbrella trials that take into account the diversity of this malignancy for a better outcome.\n\nConclusion\nThis analysis clearly shows that molecular profiling from tumor samples of patients with advanced, heavily pretreated and therapy-refractory PGC in stage IV is feasible and results in meaningful and rational therapy recommendations and strategies; however, the complex tumor biology, heterogeneity, and extreme rarity remain unique challenges for the management of PGC and need to be addressed by further studies seeking a better understanding of this malignancy. In rare diseases such as PGC where randomized trials cannot be performed easily, molecularly driven treatment approaches and strategies may be particularly useful tools and viable options.\n\nAbbreviations\nADTAndrogen deprivation therapy\n\nAKTAlpha serine/threonine-protein kinase\n\nALKAnaplastic lymphoma kinase\n\nALLAcute lymphoblastic leukemia\n\nAPCAdenomatous polyposis coli\n\nARAndrogen receptor\n\nATMAtaxia telangiectasia mutated\n\nBAP1BRCA1 associated protein‑1\n\nBRAFB‑rapidly accelerated fibrosarcoma\n\nBRCABreast cancer 1\n\nCDKN2ACyclin-dependent kinase inhibitor 2A\n\nCMLChronic myeloid leukemia\n\nCRCColorectal cancer\n\nDCRDisease control rate\n\nECOGEastern Cooperative Oncology Group\n\nEGFREpidermal growth factor receptor\n\nEMAEuropean Medicines Agency\n\nFDAFood and Drug Administration\n\nFGFRFibroblast growth factor receptor\n\nFiSHFluorescence in situ hybridization\n\nFLT3Fms like tyrosine kinase 3\n\nGISTGastrointestinal stromal tumor\n\nHER2Human epidermal growth factor receptor 2\n\nHNSCCHead and neck squamous cell carcinoma\n\nHLHodgkin lymphoma\n\nIDHIsocitrate dehydrogenase 1\n\nIHCImmunohistochemistry\n\nlossPTENLoss of phosphatase and tensin homolog\n\nMDS/MPDMyelodysplastic syndrome/myeloproliferative disorder\n\nMECMucoepidermoid carcinoma\n\nMTBMultidisciplinary tumor board\n\nmTORMammalian target of rapamycin\n\nNF1Neurofibromin 1\n\nNOSNot otherwise specified\n\nNSCLCNon-small cell lung carcinoma\n\nPARPPoly [ADP-ribose] polymerase 1\n\nPCMPrecision cancer medicine\n\nPDACPancreatic ductal adenocarcinoma\n\nPDGFRPlatelet-derived growth factor receptor\n\nPD-L1Programmed death-ligand 1\n\nPGCParotid gland carcinoma\n\nPh+Philadelphia chromosome positive\n\nPIK3CBPhosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit beta\n\np-mTORphosphorylated Mammalian target of rapamycin\n\nPRPartial response\n\nPTENPhosphatase and tensin homolog\n\nPTPN11Protein phosphatase non-receptor type 11\n\nRB1Retinoblastoma 1\n\nRCCRenal cell carcinoma\n\nSDStable disease\n\nSGCSalivary gland carcinomas\n\nSHHSonic hedgehog\n\nSMARCB1SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1\n\nSMOSmoothened\n\nSTK11Serine/threonine kinase 11\n\nTP53Tumor protein 53\n\nTRKNeurotrophin receptor kinases\n\nVEGFRVascular endothelial growth factor\n\nVHLvon Hippel-Lindau\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nFunding\nThis research did not receive any grants or funding.\n\nFunding\nOpen access funding provided by Medical University of Vienna.\n\nConflict of interest\nH. Taghizadeh, L. Müllauer, R.M. Mader, T. Füreder, and G.W. Prager declare that they have no competing interests.\n==== Refs\nReferences\n1. Holmberg KV Hoffman MP Anatomy, biogenesis and regeneration of salivary glands Monogr Oral Sci 2014 24 1 13 24862590 \n2. Amano O Mizobe K Bando Y Sakiyama K Anatomy and histology of rodent and human major salivary glands: -overview of the Japan salivary gland society-sponsored workshop Acta Histochem Cytochem 2012 45 241 250 23209333 \n3. Chason HM Downs BW Anatomy, head and neck, parotid gland 2018 Treasure Island StatPearls \n4. Seethala RR Stenman G Update from the 4th edition of the world health organization classification of head and neck tumours: tumors of the salivary gland Head Neck Pathol 2017 11 55 67 28247227 \n5. Ho K Lin H Ann DK Chu PG Yen Y An overview of the rare parotid gland cancer Head Neck Oncol 2011 3 40 21917153 \n6. Schwentner I Obrist P Thumfart W Sprinzl G Distant metastasis of parotid gland tumors Acta Otolaryngol 2006 126 4 340 345 16608783 \n7. Sood S McGurk M Vaz F Management of salivary gland tumours: United Kingdom national multidisciplinary guidelines J Laryngol Otol 2016 130 S142 S149 27841127 \n8. Wang X Luo Y Li M Yan H Sun M Fan T Management of salivary gland carcinomas—a review Oncotarget 2017 8 3946 3956 27992367 \n9. Vander Poorten V Bradley PJ Takes RP Rinaldo A Woolgar JA Ferlito A Diagnosis and management of parotid carcinoma with a special focus on recent advances in molecular biology Head Neck 2012 34 3 429 440 21618326 \n10. Spiro RH Huvos AG Berk R Strong EW Mucoepidermoid carcinoma of salivary gland origin. A clinicopathologic study of 367 cases Am J Surg 1978 136 461 468 707726 \n11. Bhattacharyya N Fried MP Determinants of survival in parotid gland carcinoma: a population-based study Am J Otolaryngol 2005 26 39 44 15635580 \n12. Hauschild A Grob JJ Demidov LV Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial Lancet 2012 380 358 365 22735384 \n13. Bang YJ Van Cutsem E Feyereislova A Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial Lancet 2010 376 9742 687 697 20728210 \n14. Kantarjian H Sawyers C Hochhaus A Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia N Engl J Med 2002 346 645 652 11870241 \n15. Von Hoff DD Stephenson JJ Jr. Rosen P Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers J Clin Oncol 2010 28 4877 4883 20921468 \n16. Konig IR Fuchs O Hansen G von Mutius E Kopp MV Eur Respir J 2017 10.1183/13993003.00391-2017 29051268 \n17. Allred DC Bustamante MA Daniel CO Immunocytochemical analysis of estrogen receptors in human breast carcinomas. Evaluation of 130 cases and review of the literature regarding concordance with biochemical assay and clinical relevance Arch Surg 1990 125 107 113 1688490 \n18. Sygut D Bien S Ziolkowska M Sporny S Immunohistochemical expression of androgen receptor in salivary gland cancers Pol J Pathol 2008 59 205 210 19391487 \n19. Dalin MG Watson PA Ho AL Morris LG Androgen Receptor Signaling in Salivary Gland Cancer Cancers (Basel) 2017 9 2 17 10.3390/cancers9020017 \n20. Nasser SM Faquin WC Dayal Y Expression of androgen, estrogen, and progesterone receptors in salivary gland tumors. Frequent expression of androgen receptor in a subset of malignant salivary gland tumors Am J Clin Pathol 2003 119 801 806 12817426 \n21. Salehinejad J Mohtasham N Bagherpour A Abbaszadeh-Bidokhty H Ghazi A Evaluation of c-kit protein (CD117) expression in common salivary gland neoplasms J Oral Maxillofac Pathol 2014 18 177 182 25328295 \n22. Tariq H Anjum S Din HU Akhtar F Diagnostic utility of C-kit protein (CD117) expression in differentiating adenoid cystic carcinoma and polymorphous low grade Adenocarcinoma Pak J Med Sci 2017 33 1376 1380 29492062 \n23. Penner CR Folpe AL Budnick SD C-kit expression distinguishes salivary gland adenoid cystic carcinoma from polymorphous low-grade adenocarcinoma Mod Pathol 2002 15 687 691 12118104 \n24. Sorensen KB Godballe C de Stricker K Krogdahl A Parotid carcinoma: expression of kit protein and epidermal growth factor receptor J Oral Pathol Med 2006 35 286 291 16630292 \n25. Yamada K Iwai K Okada Y Mori M Immunohistochemical expression of epidermal growth factor receptor in salivary gland tumours Virchows Arch A Pathol Anat Histopathol 1989 415 523 531 2508310 \n26. Shang J Shui Y Sheng L Wang K Hu Q Wei Q Epidermal growth factor receptor and human epidermal growth receptor 2 expression in parotid mucoepidermoid carcinoma: possible implications for targeted therapy Oncol Rep 2008 19 435 440 18202792 \n27. Clauditz TS Gontarewicz A Lebok P Epidermal growth factor receptor (EGFR) in salivary gland carcinomas: potentials as therapeutic target Oral Oncol 2012 48 991 996 22694907 \n28. Liu H Du L Wang R High frequency of loss of PTEN expression in human solid salivary adenoid cystic carcinoma and its implication for targeted therapy Oncotarget 2015 6 11477 11491 25909167 \n29. Ettl T Baader K Stiegler C Loss of PTEN is associated with elevated EGFR and HER2 expression and worse prognosis in salivary gland cancer Br J Cancer 2012 106 719 726 22240798 \n30. Clauditz TS Gontarewicz A Bokemeyer C Abundant expression of mTOR kinase in salivary gland tumors—potentials as therapy target? J Oral Pathol Med 2013 42 769 773 23521157 \n31. Ettl T Schwarz-Furlan S Haubner F The PI3K/AKT/mTOR signalling pathway is active in salivary gland cancer and implies different functions and prognoses depending on cell localisation Oral Oncol 2012 48 822 830 22445095 \n32. Yamamoto S Fukumoto E Yoshizaki K Platelet-derived growth factor receptor regulates salivary gland morphogenesis via fibroblast growth factor expression J Biol Chem 2008 283 23139 23149 18559345 \n33. Kato S Elkin SK Schwaederle M Genomic landscape of salivary gland tumors Oncotarget 2015 6 25631 25645 26247885 \n34. Boon E van Boxtel W Buter J Androgen deprivation therapy for androgen receptor-positive advanced salivary duct carcinoma: a nationwide case series of 35 patients in the Netherlands Head Neck 2018 40 605 613 29272069 \n35. Bell D Ferrarotto R Fox MD Analysis and significance of c-MET expression in adenoid cystic carcinoma of the salivary gland Cancer Biol Ther 2015 16 834 838 25923130 \n36. Popovtzer A Sarfaty M Limon D Metastatic salivary gland tumors: a single-center study demonstrating the feasibility and potential clinical benefit of molecular-profiling-guided therapy Biomed Res Int 2015 2015 614845 26448941 \n37. Pfeffer MR Talmi Y Catane R Symon Z Yosepovitch A Levitt M A phase II study of Imatinib for advanced adenoid cystic carcinoma of head and neck salivary glands Oral Oncol 2007 43 33 36 16757202 \n38. Hotte SJ Winquist EW Lamont E Imatinib mesylate in patients with adenoid cystic cancers of the salivary glands expressing c-kit: a Princess Margaret Hospital phase II consortium study J Clin Oncol 2005 23 585 590 15659505 \n39. Guigay JM Bidault F Temam S Antitumor activity of imatinib in progressive, highly expressing KIT adenoid cystic carcinoma of the salivary glands: A phase II study J Clin Oncol. 2007 25 18 6086 \n40. Alcedo JC Fabrega JM Arosemena JR Urrutia A Imatinib mesylate as treatment for adenoid cystic carcinoma of the salivary glands: report of two successfully treated cases Head Neck 2004 26 829 831 15350030 \n41. Chau NG Hotte SJ Chen EX A phase II study of sunitinib in recurrent and/or metastatic adenoid cystic carcinoma (ACC) of the salivary glands: current progress and challenges in evaluating molecularly targeted agents in ACC Ann Oncol 2012 23 1562 1570 22080184 \n42. Wong SJ Karrison T Hayes DN Phase II trial of dasatinib for recurrent or metastatic c-KIT expressing adenoid cystic carcinoma and for nonadenoid cystic malignant salivary tumors Ann Oncol 2016 27 318 323 26598548 \n43. Ho AL Dunn L Sherman EJ A phase II study of axitinib (AG-013736) in patients with incurable adenoid cystic carcinoma Ann Oncol 2016 27 1902 1908 27566443 \n44. Locati LD Bossi P Perrone F Cetuximab in recurrent and/or metastatic salivary gland carcinomas: A phase II study Oral Oncol 2009 45 574 578 18804410 \n45. Grunewald I Vollbrecht C Meinrath J Wardelmann E Targeted next generation sequencing of parotid gland cancer uncovers genetic heterogeneity Oncotarget 2015 6 18224 18237 26053092 \n46. Seethala RR Griffith CC Molecular pathology: predictive, prognostic, and diagnostic markers in salivary gland tumors Surg Pathol Clin 2016 9 339 352 27523965 \n47. Seymour CW Gomez H Chang CH Precision medicine for all? Challenges and opportunities for a precision medicine approach to critical illness Crit Care 2017 21 257 29047353\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0043-5325",
"issue": "133(1-2)",
"journal": "Wiener klinische Wochenschrift",
"keywords": "Head and neck cancer; Molecular guided treatment; Molecular oncology; Molecular profiling; Precision cancer medicine",
"medline_ta": "Wien Klin Wochenschr",
"mesh_terms": "D000328:Adult; D002277:Carcinoma; D006801:Humans; D058990:Molecular Targeted Therapy; D010306:Parotid Gland; D057285:Precision Medicine; D012189:Retrospective Studies",
"nlm_unique_id": "21620870R",
"other_id": null,
"pages": "32-40",
"pmc": null,
"pmid": "33296026",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": "4048853;23209333;28247227;21917153;16608783;27841127;27992367;21618326;707726;15635580;22735384;20728210;11870241;29051268;1688490;19391487;12817426;25328295;29492062;12118104;16630292;2508310;18202792;22694907;25909167;22240798;23521157;22445095;18559345;26247885;29272069;25923130;26448941;16757202;15659505;15350030;22080184;26598548;27566443;18804410;26053092;27523965;29047353",
"title": "Molecularly guided treatment of metastatic parotid gland carcinoma in adults.",
"title_normalized": "molecularly guided treatment of metastatic parotid gland carcinoma in adults"
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"abstract": "We analyzed the findings on plain abdominal radiographs in 24 patients who had adverse gastrointestinal reactions after chemotherapy with cytosine-arabinoside (Ara-C) for treatment of acute leukemia or non-Hodgkin lymphoma. Ara-C was given with vincristine, VP 16-213, daunorubicin, amsacrine, adriamycin, or corticosteroids in various combinations and dosages. The abnormalities noted on plain abdominal radiographs included paralytic ileus (73%), cecal distension (38%), pneumatosis intestinalis (27%), thickened loops of small bowel (19%), and pneumoperitoneum (8%). One patient had small-bowel ileus simulating an obstruction. In 23%, death was directly related to gastrointestinal complications. Bowel wall erosions, necrosis, and transmural or submucosal hemorrhage were the main findings at autopsy. This experience suggests that plain abdominal radiographs are useful in the diagnosis of gastrointestinal complications associated with chemotherapy with Ara-C.",
"affiliations": "Department of Diagnostic Radiology, University Medical Centre, Leiden, The Netherlands.",
"authors": "Tjon A Tham|R T|RT|;Vlasveld|L T|LT|;Willemze|R|R|",
"chemical_list": "D003561:Cytarabine",
"country": "United States",
"delete": false,
"doi": "10.2214/ajr.154.1.2104733",
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"issue": "154(1)",
"journal": "AJR. American journal of roentgenology",
"keywords": null,
"medline_ta": "AJR Am J Roentgenol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002429:Cecal Diseases; D003561:Cytarabine; D005260:Female; D005767:Gastrointestinal Diseases; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D007415:Intestinal Obstruction; D007418:Intestinal Pseudo-Obstruction; D008297:Male; D008875:Middle Aged; D010538:Peritonitis; D011006:Pneumatosis Cystoides Intestinalis; D011027:Pneumoperitoneum; D011859:Radiography; D013272:Stomach Diseases",
"nlm_unique_id": "7708173",
"other_id": null,
"pages": "95-8",
"pmc": null,
"pmid": "2104733",
"pubdate": "1990-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Gastrointestinal complications of cytosine-arabinoside chemotherapy: findings on plain abdominal radiographs.",
"title_normalized": "gastrointestinal complications of cytosine arabinoside chemotherapy findings on plain abdominal radiographs"
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"companynumb": "NL-PFIZER INC-2021290954",
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"abstract": "OBJECTIVE\nOver the last years, there have been several reports on the occurrence of acute liver damage (ALD) in patients affected with Graves' ophthalmopathy (GO) receiving intravenous glucocorticoids (ivGCs). This article is aimed at reviewing the literature on this specific topic and reporting two new cases of ALD occurring in GO patients while on ivGCs.\n\n\nMETHODS\nThe terms \"glucocorticoid therapy\" and \"Graves' Ophthalmopathy\"/\"Graves' Orbitopathy\"/\"Thyroid eye disease\" were used both separately and in conjunction with the terms \"liver disease,\" \"liver damage,\" \"hepatotoxicity,\" \"liver failure,\" to search MEDLINE for articles published since the first report of ALD in 2000 and up to 2015.\n\n\nRESULTS\nALD [defined as an increase in alanine aminotransferase (ALT) >300 U/L] during or after completion of ivGCs has been so far reported in 17 fully documented cases. Overall, one-half of those patients were diagnosed as having autoimmune hepatitis (AIH) and in the vast majority of the remaining cases a diagnosis of methylprednisolone(MP)-induced hepatotoxicity was suspected. The clinical course of liver injury varied from asymptomatic hypertransaminasemia in the vast majority of patients to fatal hepatic failure in four patients receiving higher (>8 g) cumulative doses of MP.\n\n\nCONCLUSIONS\nThe overall risk of ALD is relatively low (~1 %), and seems higher using a single dose >0.5 g and a cumulative dose >8.5 g MP. Whenever ivGC treatment is required, serum liver enzymes, viral hepatitis markers, and autoantibodies related to AIH should be obtained prior to ivGC administration. Liver function should be monitored during ivGC and up to 6 months after the end of treatment. Prolonging observation after 6 months is likely unnecessary, since all cases of ALD so far reported always occurred well within this term.",
"affiliations": "Dipartimento di Medicina Clinica e Sperimentale, University of Messina, Messina, Italy. mmoleti@unime.it.;Dipartimento di Medicina Clinica e Sperimentale, University of Messina, Messina, Italy.;Dipartimento di Medicina Clinica e Sperimentale, University of Messina, Messina, Italy.;Dipartimento di Patologia Umana dell'adulto e dell'età evolutiva, University of Messina, Messina, Italy.;Dipartimento di Scienze Radiologiche, Sezione di Medicina Nucleare University of Messina, Messina, Italy.;Dipartimento di Medicina, University of Perugia, Perugia, Italy.;Dipartimento di Medicina, University of Perugia, Perugia, Italy.;Dipartimento di Medicina Clinica e Sperimentale, University of Pisa, Pisa, Italy.;Dipartimento di Medicina Clinica e Sperimentale, University of Messina, Messina, Italy.;Dipartimento di Medicina Clinica e Sperimentale, University of Messina, Messina, Italy.;Dipartimento di Medicina Clinica e Sperimentale, University of Pisa, Pisa, Italy.",
"authors": "Moleti|Mariacarla|M|http://orcid.org/0000-0002-8686-1615;Giuffrida|Giuseppe|G|;Sturniolo|Giacomo|G|;Squadrito|Giovanni|G|;Campennì|Alfredo|A|;Morelli|Silvia|S|;Puxeddu|Efisio|E|;Sisti|Eleonora|E|;Trimarchi|Francesco|F|;Vermiglio|Francesco|F|;Marinò|Michele|M|",
"chemical_list": "D005938:Glucocorticoids; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1007/s12020-016-0928-3",
"fulltext": null,
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"issn_linking": "1355-008X",
"issue": "54(1)",
"journal": "Endocrine",
"keywords": "Acute liver damage; Graves’ ophthalmopathy; Hepatotoxicity; Intravenous glucocorticoid therapy; Methylprednisolone",
"medline_ta": "Endocrine",
"mesh_terms": "D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D005938:Glucocorticoids; D049970:Graves Ophthalmopathy; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged",
"nlm_unique_id": "9434444",
"other_id": null,
"pages": "259-268",
"pmc": null,
"pmid": "27003434",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "1600269;9161506;17723915;11314743;24617953;16926305;25576458;25661744;24913238;19159178;11502779;24432992;15952415;19627724;22216984;24606088;19399803;17465867;10566758;10907999;23768844;22058081;25740065;12144908;15998777;19935411;15186621;24126481;19421243;16889639;21239515;3053889;18230831;22140391;12003403;24776622;26221141;15320978;16923576;21148573;23587873;23980907;22029719;18803363;17452966;24935270;18341379;17299076;26090805;15967341;25751109;23038682;24761710;25722226",
"title": "Acute liver damage following intravenous glucocorticoid treatment for Graves' ophthalmopathy.",
"title_normalized": "acute liver damage following intravenous glucocorticoid treatment for graves ophthalmopathy"
} | [
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"companynumb": "IT-PFIZER INC-2016250553",
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"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
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"abstract": "Bevacizumab is a drug that is widely used for the first-line treatment of metastatic colorectal cancer (mCRC). Bevacizumab neutralizes vascular endothelial growth factor and can lead to proteinuria and renal damage. In this case, experience on full dose short-time treatment of bevacizumab in a patient under immunosuppressive treatment for renal transplantation with chronic renal failure has been shared. The patients were diagnosed with mCRC 7 months ago. The patient had multiple liver metastases at the time of the diagnosis. He had a history of renal transplantation 2 years ago because of renal failure, and he had been under immunosuppressive treatment for this reason. 5-fluorouracil-leucovorin-irinotecan -bevacizumab regimen was begun for the treatment of mCRC. The dose of bevacizumab was 5 mg/kg/day for 14 days. There was 2.5 g/day of proteinuria at the start of the treatment. However, renal dysfunction progressed, and proteinuria increased to 4 g/day in the 3rd month of treatment. In this case, the experience of using bevacizumab in a patient under immunosuppressive treatment for renal transplantation with chronic failure has been presented.",
"affiliations": "Department of Medical Oncology, Akdeniz University School of Medicine, Antalya, Turkey.",
"authors": "Müsri|Fatma Yalcin|FY|;Mutlu|Hasan|H|;Eryılmaz|Melek Karakurt|MK|;Salim|Derya Kıvrak|DK|;Coşkun|Hasan Şenol|HŞ|",
"chemical_list": "D000068258:Bevacizumab; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "India",
"delete": false,
"doi": "10.4103/0973-1482.168996",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "11(4)",
"journal": "Journal of cancer research and therapeutics",
"keywords": null,
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin; D015179:Colorectal Neoplasms; D005472:Fluorouracil; D006801:Humans; D000077146:Irinotecan; D016030:Kidney Transplantation; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D051437:Renal Insufficiency",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "1018-20",
"pmc": null,
"pmid": "26881574",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Experience of bevacizumab in a patient with colorectal cancer after renal transplantation.",
"title_normalized": "experience of bevacizumab in a patient with colorectal cancer after renal transplantation"
} | [
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"companynumb": "TR-PFIZER INC-2021219486",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "FLUOROURACIL"
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... |
{
"abstract": "BACKGROUND\nRetreatment with pegylated interferon (peg-IFN) and ribavirin (RBV) results in poor sustained virological response (SVR) rates in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. There are limited data regarding the use of telaprevir plus peg-IFN/RBV in this population.\n\n\nMETHODS\nHIV type 1-infected patients who previously failed ≥12 weeks of peg-IFN/RBV for HCV genotype 1 coinfection were enrolled in a single-arm, phase 2 trial. Patients with cirrhosis and previous null response were excluded. Authorized antiretrovirals were tenofovir, emtricitabine, efavirenz, atazanavir, and raltegravir. All patients received peg-IFN alfa-2a (180 µg/week) plus RBV (1000-1200 mg/day) for 4 weeks, followed by telaprevir (750 mg or 1125 mg every 8 hours with efavirenz) plus peg-IFN/RBV for 12 weeks and peg-IFN/RBV for 32-56 weeks according to virological response at week 8. The primary endpoint was the SVR rate at 24 weeks after the end of treatment (SVR24).\n\n\nRESULTS\nSixty-nine patients started treatment; SVR24 was achieved in 55 (80% [95% confidence interval, 68%-88%). SVR24 was not influenced by baseline fibrosis stage, IL28B genotype, antiretroviral regimen, HCV subtype, CD4 cell count, previous response to HCV treatment, HCV RNA level, or HCV RNA decline at week 4. HCV treatment was discontinued for adverse events (AEs) in 20% of patients, including cutaneous (4%), psychiatric (4%), hematological (6%), and other AEs (6%). Peg-IFN or RBV dose reduction was required in 23% and 43% of patients, respectively. Seventy percent of patients required erythropoietin, blood transfusions, or RBV dose reduction for anemia. Two patients died during the study. No HIV breakthrough was observed.\n\n\nCONCLUSIONS\nDespite a high discontinuation rate related to toxicity, a substantial proportion of treatment-experienced HIV-coinfected patients achieved SVR24 with a telaprevir-based regimen. Clinical Trials Registration. NCT01332955.",
"affiliations": null,
"authors": "Cotte|Laurent|L|;Braun|Joséphine|J|;Lascoux-Combe|Caroline|C|;Vincent|Corine|C|;Valantin|Marc-Antoine|MA|;Sogni|Philippe|P|;Lacombe|Karine|K|;Neau|Didier|D|;Aumaitre|Hugues|H|;Batisse|Dominique|D|;de Truchis|Pierre|P|;Gervais|Anne|A|;Michelet|Christian|C|;Morlat|Philippe|P|;Vittecoq|Daniel|D|;Rosa|Isabelle|I|;Bertucci|Inga|I|;Chevaliez|Stéphane|S|;Aboulker|Jean-Pierre|JP|;Molina|Jean-Michel|JM|;|||",
"chemical_list": "D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; C100416:peginterferon alfa-2a",
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"issue": "59(12)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "HCV retreatment; HIV/HCV coinfection; direct acting agent; telaprevir",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000998:Antiviral Agents; D060085:Coinfection; D005260:Female; D015658:HIV Infections; D019698:Hepatitis C, Chronic; D006801:Humans; D016898:Interferon-alpha; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D016896:Treatment Outcome",
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"pubdate": "2014-12-15",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Telaprevir for HIV/hepatitis C virus-coinfected patients failing treatment with pegylated interferon/ribavirin (ANRS HC26 TelapreVIH): an open-label, single-arm, phase 2 trial.",
"title_normalized": "telaprevir for hiv hepatitis c virus coinfected patients failing treatment with pegylated interferon ribavirin anrs hc26 telaprevih an open label single arm phase 2 trial"
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"abstract": "BACKGROUND\nFingolimod is used for immune therapy in patients with multiple sclerosis. Long-term treatment is associated with a small increase in the risk of herpes virus reactivation and respiratory tract infections. Patients with coronavirus disease 2019 (COVID-19) under Fingolimod treatment have not been described.\n\n\nRESULTS\nWe report a 57-year old female patient with a relapsing remitting multiple sclerosis under fingolimod treatment who experienced a severe COVID-19 infection in March 2020 (Extended Disability Status Scale: 2.0). Having peripheral lymphopenia typical for fingolimod treatment (total lymphocytes 0.39/nL [reference range 1.22-3.56]), the patient developed bilateral interstitial pneumonia with multiple ground-glass opacities on chest CT. Fingolimod medication was stopped. On the intensive care unit, non-invasive ventilation was used to provide oxygen and ventilation support regularly. Over the following two days, oxygenation improved, and the patient was transferred to a normal ward five days after admission.\n\n\nCONCLUSIONS\nThe implications fingolimod has on COVID-19 are complex. As an S1P analogue, fingolimod might enhance lung endothelial cell integrity. In addition, in case of a so-called cytokine storm, immunomodulation might be beneficial to reduce mortality. Future studies are needed to explore the risks and therapeutic effects of fingolimod in COVID-19 patients.",
"affiliations": "Department of Neurology, University Hospital, Goethe University, Schleusenweg 2-16, Frankfurt am Main 60528, Germany. Electronic address: foerch@em.uni-frankfurt.de.;Department of Neurology, University Hospital, Goethe University, Schleusenweg 2-16, Frankfurt am Main 60528, Germany.;Radiologie Sachsenhausen GmbH, Frankfurt am Main, Germany.;Department of Internal Medicine, University Hospital, Goethe University, Frankfurt am Main, Germany.;Department of Anesthesiology, Intensive Care and Pain Therapy, University Hospital, Goethe University, Frankfurt am Main, Germany.",
"authors": "Foerch|Christian|C|;Friedauer|Lucie|L|;Bauer|Boris|B|;Wolf|Timo|T|;Adam|Elisabeth H|EH|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2020.102180",
"fulltext": null,
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"issn_linking": "2211-0348",
"issue": "42()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "COVID-19; Critical care; Fingolimod; Multiple sclerosis; Viral infection",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D000069340:Deprescriptions; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D063087:Noninvasive Ventilation; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "102180",
"pmc": null,
"pmid": "32408155",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports",
"references": "32085846;25419615;21339486;31986264;23449739;20089952",
"title": "Severe COVID-19 infection in a patient with multiple sclerosis treated with fingolimod.",
"title_normalized": "severe covid 19 infection in a patient with multiple sclerosis treated with fingolimod"
} | [
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"abstract": "Hypocalcemia is a known risk following bariatric surgery and can contribute to the development of osteoporosis. Osteoporosis is commonly treated with denosumab, though denosumab can exacerbate underlying abnormalities in calcium homeostasis. We present the case of a 59-year-old female with severe hypocalcemia who had been treated with denosumab for osteoporosis three months before and had Billroth II gastric bypass surgery 15 years before, for bariatric purposes. Intravenous calcium supplementation was used to correct the initial electrolyte abnormality, and the patient was able to maintain appropriate calcium levels on high doses of oral calcium before discharge. Denosumab-induced hypocalcemia has been previously reported in patients with predisposing conditions including chronic kidney disease, primary sclerosing cholangitis, Crohn's disease, and a history of sleeve gastrectomy for marginal gastric ulcers. A few cases of hypocalcemia have been reported in patients with a history of bariatric surgery secondary to vitamin D deficiency, but this report is unique in demonstrating denosumab-induced hypocalcemia after bariatric surgery with normal vitamin D levels, suggesting a primary malabsorption of calcium. The risk of severe hypocalcemia should be considered before initiating denosumab to treat osteoporosis in patients with a history of bariatric surgery. If denosumab is initiated, serum calcium levels should be closely monitored, and patients should be educated about the importance of adherence to calcium supplementation.",
"affiliations": "Sidney Kimmel Medical College, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA 19107, USA.;Lankenau Medical Center, 100 East Lancaster Avenue, Wynnewood, PA 19096, USA.;Lankenau Medical Center, 100 East Lancaster Avenue, Wynnewood, PA 19096, USA.",
"authors": "Schmucker|Abigail M|AM|https://orcid.org/0000-0002-2813-1868;Green|Dina E|DE|;Montemuro|Philip M|PM|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1155/2020/8833723",
"fulltext": "\n==== Front\nCase Rep Endocrinol\nCase Rep Endocrinol\nCRIE\nCase Reports in Endocrinology\n2090-6501 2090-651X Hindawi \n\n10.1155/2020/8833723\nCase Report\nDenosumab-Induced Hypocalcemia after Billroth II Gastric Bypass Surgery\nhttps://orcid.org/0000-0002-2813-1868Schmucker Abigail M. abigail.m.schmucker@gmail.com\n1\n Green Dina E. \n2\n Montemuro Philip M. \n2\n \n1Sidney Kimmel Medical College, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA 19107, USA\n\n2Lankenau Medical Center, 100 East Lancaster Avenue, Wynnewood, PA 19096, USA\nAcademic Editor: Takeshi Usui\n\n\n2020 \n23 7 2020 \n2020 883372329 4 2020 4 7 2020 13 7 2020 Copyright © 2020 Abigail M. Schmucker et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Hypocalcemia is a known risk following bariatric surgery and can contribute to the development of osteoporosis. Osteoporosis is commonly treated with denosumab, though denosumab can exacerbate underlying abnormalities in calcium homeostasis. We present the case of a 59-year-old female with severe hypocalcemia who had been treated with denosumab for osteoporosis three months before and had Billroth II gastric bypass surgery 15 years before, for bariatric purposes. Intravenous calcium supplementation was used to correct the initial electrolyte abnormality, and the patient was able to maintain appropriate calcium levels on high doses of oral calcium before discharge. Denosumab-induced hypocalcemia has been previously reported in patients with predisposing conditions including chronic kidney disease, primary sclerosing cholangitis, Crohn's disease, and a history of sleeve gastrectomy for marginal gastric ulcers. A few cases of hypocalcemia have been reported in patients with a history of bariatric surgery secondary to vitamin D deficiency, but this report is unique in demonstrating denosumab-induced hypocalcemia after bariatric surgery with normal vitamin D levels, suggesting a primary malabsorption of calcium. The risk of severe hypocalcemia should be considered before initiating denosumab to treat osteoporosis in patients with a history of bariatric surgery. If denosumab is initiated, serum calcium levels should be closely monitored, and patients should be educated about the importance of adherence to calcium supplementation.\n\nThomas Jefferson UniversityPhiladelphia University Open Access Fund\n==== Body\n1. Introduction\nWith rising rates of obesity globally, bariatric surgery for weight loss has become an increasingly safe and effective option for managing excess weight and associated metabolic and mechanical complications [1, 2]. While bariatric surgical procedures continue to be modified to maximize weight loss while minimizing morbidity and mortality, they are not without risk [1]. Suboptimal preoperative nutrition, anatomical changes, and postoperative dietary constraints can lead to significant micronutrient and vitamin deficiencies after bariatric surgery, including hypocalcemia [2].\n\nThe combination of these nutritional deficiencies with mechanical and hormonal changes resulting from bariatric surgery can also contribute to the development of osteoporosis [3]. Antiresorptive therapies such as bisphosphonates and denosumab are first-line treatments for osteoporosis, yet they also pose a risk of hypocalcemia in predisposed patients, ranging from minor and asymptomatic to life-threatening conditions [4, 5]. Hypocalcemia is a known risk of both bariatric surgical procedures and antiresorptive osteoporosis therapies [2, 4, 6], but the hypocalcemia risk of these two factors combined and the optimal treatment of those with osteoporosis secondary to a history of bariatric surgery have received little attention in the literature.\n\nIn this report, we present the case of a 59-year-old female who developed severe hypocalcemia three months after treatment with denosumab for osteoporosis and fifteen years after Billroth II gastric bypass surgery. This case was prepared in accordance with the CARE guidelines for case reports (see Appendix 1 in Supplementary Materials for CARE checklist).\n\n2. Case Presentation\nA 59-year-old postmenopausal woman with a past medical history of Billroth II gastric bypass surgery 15 years before for bariatric purposes, Barrett esophagus, pericarditis secondary to suspected rheumatologic disease status treated with a pericardial window 3 years before, rheumatoid arthritis with negative rheumatoid factor, paroxysmal atrial fibrillation, amiodarone-induced hypothyroidism, and osteoporosis treated with denosumab 3 months before was referred to the emergency department by her endocrinologist after outpatient labs revealed profound hypocalcemia, hypophosphatemia, and hypomagnesemia. The patient had recently returned from vacation, where she experienced 2-3 episodes of diarrhea. She reported compliance to her medications, which included 50,000 IU ergocalciferol daily and 630 mg calcium citrate 2-3 times daily, apart from taking a decreased dose of calcium for the last 4 days of her vacation since she was running low on pills. She noted fatigue and intermittent tingling in her hands, feet, and perioral region for 2-3 days prior to admission. She denied weight loss, fever, muscle cramping, seizures, loss of consciousness, or lightheadedness.\n\nOn presentation, the patient was afebrile with a temperature of 98.2ºF, blood pressure of 136/74 mmHg, heart rate of 71 beats/min, and respiratory rate of 15 breaths/min. Her oxygen saturation was 100% on room air. Physical examination revealed a well-appearing woman with a body mass index (BMI) of 30 kg/m2 in no acute distress. Neck was supple with no thyromegaly. There were no abnormalities on cardiac or pulmonary exam. Abdomen was soft, nontender, and nondistended with normal bowel sounds. Patient had a positive Chvostek's sign. No muscle twitches or spasms were appreciated. Strength, sensation, reflexes, and cranial nerves were intact. The patient had no signs of confusion or psychosis.\n\nBlood tests from the emergency department revealed a calcium of 5.8 mg/dL, phosphorus of <1 mg/dL, and magnesium of 1.7 mg/dL. Albumin was 3.8 g/dL, so the corrected calcium was 6.0 mg/dL. Ionized calcium was 0.8 mg/dL. Parathyroid hormone was 136 ng/L. 25-Hydroxy vitamin D was normal at 46 ng/mL, and 1-25-hydroxy vitamin D was normal at 30 pg/mL. Urinalysis was within normal limits, and urine calcium was <2 mg/dL. Creatinine was 0.61 mg/dL, and blood urea nitrogen was 11 mg/dL. TSH was normal at 0.78 μU/mL. An electrocardiogram performed in the emergency department showed normal sinus rhythm with a corrected QT interval of 493 ms.\n\nIn the emergency department, the patient was given 2 g of IV magnesium sulfate, 30 mmol of IV sodium phosphate, and 1 g of IV calcium gluconate. During her 4-day hospital stay, the patient continued to receive IV calcium, as well as oral calcitriol, phosphate, and magnesium. When she was able to consistently maintain serum calcium of at least 8.0 mg/dL on oral calcium citrate supplementation, she was discharged with a calcium level of 8.0 mg/dL, magnesium of 1.9 mg/dL, and phosphorus of 2.3 mg/dL. She was instructed to take calcium citrate of 1260 mg 4 times daily, calcitriol of 0.25 mcg 2 times daily, phosphorus of 250 mg 3 times daily, and magnesium oxide of 400 mg 2 times daily and to be followed up closely with her endocrinologist. Since discharge, the patient has been able to maintain adequate calcium levels on a low dose of calcium supplementation, and she is interested in considering further doses of denosumab.\n\n3. Discussion\nThe risk of hypocalcemia following denosumab use for osteoporosis has been demonstrated in multiple case reports and case series for patients with chronic kidney disease [7–10] and in individual case reports for patients with primary sclerosing cholangitis [11], Crohn's disease [8, 12, 13], and a history of sleeve gastrectomy for marginal gastric ulcers [12]. A few cases of hypocalcemia with denosumab have been reported in patients with a history of bariatric surgery, but each of these was likely secondary to vitamin D deficiency [14, 15]. In our case, normal active and storage forms of vitamin D, low phosphate, and normal kidney function tests suggested that the hypocalcemia was not due to renal failure or vitamin D deficiency. With these etiologies excluded, the most likely cause of hypocalcemia was primary calcium malabsorption from the bariatric Billroth II procedure 15 years before, exacerbated by denosumab use 3 months before and insufficient calcium supplementation during the week prior to admission.\n\nBillroth II gastrectomy is a form of gastric bypass surgery often used for refractory peptic ulcer disease and gastric adenocarcinoma, but it can also be used for weight loss since it reduces the volume of the stomach, causing early satiety [16]. Due to a combination of anatomical changes, postoperative dietary changes, and suboptimal preoperative nutrition, many patients develop micronutrient deficiencies after bariatric surgery [2], and Billroth II procedure has been shown to cause calcium and vitamin D absorption disturbances [17]. Because of the risk of hypocalcemia following bariatric surgery, calcium supplementation and vitamin D supplementation are recommended to prevent postoperative hypocalcemia [14].\n\nEven with adequate supplementation, the malabsorption resulting from bariatric surgery, combined with mechanical and hormonal factors related to weight loss, predisposes patients to osteoporosis after bariatric surgery [3]. Denosumab, a common first-line treatment for osteoporosis, is a monoclonal antibody approved for prevention of skeletal-related events in postmenopausal women at risk for osteoporosis (as Prolia®) and is given as a subcutaneous injection every six months [4, 18]. Denosumab functions by inhibiting osteoclast-mediated bone resorption by binding to the receptor activator of nuclear factor kappa B ligand (RANKL), thus preventing RANKL from binding to its receptor. As a result, less skeletal calcium is released into the circulation [19]. Denosumab is known to exacerbate existing hypocalcemia, so correction of preexisting hypocalcemia is suggested prior to administration. Additionally, monitoring of calcium, phosphorus, and magnesium is recommended, and supplementation with at least 1000 mg daily of calcium and 400 IU of vitamin D is recommended, particularly during the first 14 days after administration [20].\n\nOur patient experienced profound hypocalcemia 15 years after bariatric surgery and 3 months after denosumab administration. Prior to this episode, the patient was on a longstanding dose of 50,000 IU ergocalciferol daily, as well as 630 mg calcium citrate 2-3 times daily, which is well within the recommendations of the Prolia® insert [20]. She was closely monitored by her rheumatologist and endocrinologist during the interval immediately after denosumab administration, and she never experienced profound hypocalcemia during this time. Considering our patient had two separate indications for calcium and vitamin D supplementation, perhaps she needed higher doses of oral supplements, or she was particularly susceptible to a few days of a decreased calcium dose while on vacation.\n\nOne previous study sought to identify risks for denosumab-induced hypocalcemia and found no significant associations between clinical parameters and development of hypocalcemia [5]. Notably, however, previous gastrointestinal surgeries were not included among the clinical parameters they assessed. The study concluded that high baseline bone turnover, as evidenced by increased serum bone turnover markers, was associated with denosumab-induced hypocalcemia [5]. Given that our patient likely had a decreased ability to absorb calcium via the gastrointestinal tract, it seems reasonable to hypothesize that she had high baseline bone turnover.\n\nStrengths of this case include the fact that the patient was a reliable historian with a well-documented surgical and medical history within the electronic medical record. Additionally, her established outpatient endocrinologist followed her in the hospital, allowing for continuity of care and effective outpatient follow-up. A weakness of the case is that there is no way to parse out the relative contribution to hypocalcemia of each potential factor—denosumab use, chronic absorption issues from prior bariatric surgery, and missed calcium supplementation and diarrhea in the days leading up to admission. Additionally, given the timing of the patient's bariatric surgery relative to the current episode, we do not have access to the degree of her weight loss after the surgery; however, based on the history from the patient and a current BMI of 30, we do not suspect that malabsorptive issues were a result of an overly aggressive bariatric surgery. Further research is needed to determine the risk of denosumab-induced hypocalcemia for various bariatric surgical techniques, as well as to determine a safe and cost-effective way to select patients for extended calcium monitoring after denosumab administration.\n\nThis case demonstrates that the risk of profound hypocalcemia should be weighed when considering initiation of denosumab in a patient with a history of bariatric surgery. While bariatric surgery has been shown to decrease bone mineral density, a 2012 study in the British Medical Journal showed that bariatric surgery does not have a significant effect on fracture risk, at least over the short term [21]. So, perhaps, treatment of osteoporosis secondary to bariatric surgery can be less aggressive than treatment of primary osteoporosis. For those patients with a bariatric surgery history who are started on denosumab for osteoporosis, monitoring of calcium, phosphorus, and magnesium should be extended beyond the 14-day interval recommended in the Prolia® insert, and higher doses of calcium, phosphorus, magnesium, and vitamin D should be considered than those recommended for general denosumab use. Finally, patients should be educated about the importance of long-term adherence to supplementation, as well as what symptoms should prompt them to visit the emergency department.\n\nAcknowledgments\nThis work was supported in part by Thomas Jefferson University and Philadelphia University Open Access Fund.\n\nData Availability\nNo data were used to support this study.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nSupplementary Materials\nSupplementary Materials Appendix 1: CARE checklist.\n\nClick here for additional data file.\n==== Refs\n1 Spiegel H.-U. Skawran S. From longitudinal gastric resection to sleeve gastrectomy-revival of a previously established surgical procedure Journal of Gastrointestinal Surgery 2011 15 1 219 228 10.1007/s11605-010-1293-9 2-s2.0-78751579144 20725800 \n2 Shah M. Sharma A. Wermers R. A. Kennel K. A. Kellogg T. A. Mundi M. S. Hypocalcemia after bariatric surgery: prevalence and associated risk factors Obesity Surgery 2017 27 11 2905 2911 10.1007/s11695-017-2705-7 2-s2.0-85019000669 28470489 \n3 Jammah A. Endocrine and metabolic complications after bariatric surgery Saudi Journal of Gastroenterology 2015 21 5 269 277 10.4103/1319-3767.164183 2-s2.0-84944049040 26458852 \n4 Tu K. N. Lie J. D. Wan C. K. V. Osteoporosis: a review of treatment options A Peer-Reviewed Journal for Formulary Management 2018 43 2 92 104 \n5 Ishikawa K. Nagai T. Sakamoto K. High bone turnover elevates the risk of denosumab-induced hypocalcemia in women with postmenopausal osteoporosis Therapeutics and Clinical Risk Management 2016 12 1831 1840 10.2147/tcrm.s123172 2-s2.0-85007524737 27980413 \n6 Qi W.-X. Lin F. He A.-N. Tang L.-N. Shen Z. Yao Y. Incidence and risk of denosumab-related hypocalcemia in cancer patients: a systematic review and pooled analysis of randomized controlled studies Current Medical Research and Opinion 2013 29 9 1067 1073 10.1185/03007995.2013.813840 2-s2.0-84882759793 23745518 \n7 Cernes R. Barnea Z. Biro A. Zandman-Goddard G. Katzir Z. Severe hypocalcemia following a single denosumab injection Israel Medical Association Journal 2017 19 11 719 721 29185289 \n8 Strickling J. Wilkowski M. J. Severe, symptomatic hypocalcemia due to denosumab administration: treatment and clinical course Case Reports in Nephrology and Dialysis 2019 9 1 33 41 10.1159/000499824 2-s2.0-85064898797 31192226 \n9 Bhanot R. D. Kaur J. Bhat Z. Severe hypocalcemia and dramatic increase in parathyroid hormone after denosumab in a dialysis patient: a case report and review of the literature Case Reports in Nephrology 2019 2019 1 4 10.1155/2019/3027419 \n10 Jalleh R. Basu G. Le Leu R. Jesudason S. Denosumab-induced severe hypocalcaemia in chronic kidney disease Case Reports in Nephrology 2018 2018 1 7 10.1155/2018/7384763 \n11 Yasuda Y. Iwama S. Arima H. Severe hypocalcemia following denosumab treatment in a patient with secondary osteoporosis associated with primary sclerosing cholangitis Endocrine Journal 2019 66 3 271 275 10.1507/endocrj.ej18-0545 2-s2.0-85063934348 30713246 \n12 Kalayanamitra R. Yaghnam I. Patel R. Groff A. Jain R. The calcium culprit: a case of denosumab-induced hypocalcemia Cureus 2019 11 10.7759/cureus.4768 \n13 Chandurkar V. Marliss E. B. Multiple factors in recurrent symptomatic hypocalcemia following denosumab in a patient receiving home parenteral nutrition Journal of Parenteral and Enteral Nutrition 2016 40 5 734 738 10.1177/0148607115571968 2-s2.0-84976272005 25681492 \n14 Miñambres I. Chico A. Pérez A. Severe hypocalcemia due to vitamin D deficiency after extended roux-en-Y gastric bypass Journal of Obesity 2011 2011 1 3 10.1155/2011/141024 2-s2.0-84877686814 \n15 Baptista Lopes V. Robbrecht D. van Thiel S. van Guldener C. [Symptomatic hypocalcaemia on denosumab use] Ned Tijdschr Geneeskd 2013 157 29 p. A6159 \n16 Weledji E. P. Overview of gastric bypass surgery International Journal of Surgery Open 2016 5 11 19 10.1016/j.ijso.2016.09.004 2-s2.0-84990053706 \n17 Fukuda M. Shibata H. Hatakeyama K. Difference in calcium metabolism following billroth-I and billroth-II procedures for gastric and duodenal ulcers The Japanese Journal of Surgery 1979 9 4 295 303 10.1007/bf02468629 2-s2.0-0018626329 544888 \n18 Muqeet Adnan M. Morton J. Hashmi S. Abdul Mujeeb S. Kern W. Cowley B. J. Anti-GBM of pregnancy: acute renal failure resolved after spontaneous abortion, plasma exchange, hemodialysis, and steroids Case Reports in Nephrology 2014 2014 1 4 10.1155/2014/243746 \n19 Laskowski L. K. Goldfarb D. S. Howland M. A. Kavcsak K. Lugassy D. M. Smith S. W. A RANKL wrinkle: denosumab-induced hypocalcemia Journal of Medical Toxicology 2016 12 3 305 308 10.1007/s13181-016-0543-y 2-s2.0-84961214226 26987988 \n20 Amgen Prolia Highlights of Prescribing Information 2010 Thousand Oaks, CA, USA Amgen \n21 Angrisani L. Santonicola A. Iovino P. Formisano G. Buchwald H. Scopinaro N. Bariatric surgery worldwide 2013 Obesity Surgery 2015 25 10 1822 1832 10.1007/s11695-015-1657-z 2-s2.0-84940962819 25835983\n\n",
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"title": "Denosumab-Induced Hypocalcemia after Billroth II Gastric Bypass Surgery.",
"title_normalized": "denosumab induced hypocalcemia after billroth ii gastric bypass surgery"
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... |
{
"abstract": "Children with central nervous system (CNS) toxicity during therapy for acute lymphoblastic leukaemia (ALL) are at risk for treatment modifications, long-term sequelae and even higher mortality. A better understanding of CNS symptoms and their complications improves the potential to prevent and treat them.\n\n\n\nPatient files from 649 children treated with Nordic Society of Pediatric Hematology and Oncology ALL92 and ALL2000 protocols in Finland were reviewed retrospectively for any acute CNS symptom. Detailed data on symptoms, examinations and treatment of the underlying CNS complications were collected from the medical records. Disease-related and outcome data were retrieved from the Nordic leukaemia registry.\n\n\n\nAltogether, 13% (86) of patients with ALL had acute CNS symptoms. Most symptoms (64%) occurred during the first 2 months of therapy. Posterior reversible encephalopathy syndrome was the most frequent complication (4.5%). Cerebrovascular events were diagnosed in 10 cases (1.6%), while methotrexate-related stroke-like syndrome (SLS) was observed in only one patient (0.2%). CNS symptoms due to systemic or unclear conditions, especially sepsis, were important for differential diagnosis. CNS leukaemia was associated with CNS symptoms (hazard ratio [HR] = 4.03; P = .003), and epilepsy was a common sequel of CNS complications (19%).\n\n\n\nAcute CNS symptoms are common during ALL therapy, occurring mainly during the first 2 months of treatment. Patients with CNS leukaemia at diagnosis are at a higher risk for CNS toxicity. Despite intensive CNS-directed methotrexate treatment, SLS was diagnosed extremely rarely in our series.",
"affiliations": "Division of Pediatric Hematology and Oncology and Stem Cell Transplantation, Helsinki University Hospital and Helsinki University, Helsinki, Finland.;Department of Children and Adolescents, Oulu University Hospital and PEDEGO Research Unit, University of Oulu, Oulu, Finland.;Department of Pediatrics and Adolescent Medicine, Turku University Hospital and Turku University, Turku, Finland.;Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.;Department of Pediatrics, Tampere University Hospital, Tampere, Finland.;Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland.;Division of Child Neurology, Helsinki University Hospital and Helsinki University, Helsinki, Finland.;Department of Radiology, Helsinki Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland.;Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.;Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.;Division of Pediatric Hematology and Oncology and Stem Cell Transplantation, Helsinki University Hospital and Helsinki University, Helsinki, Finland.",
"authors": "Banerjee|Joanna|J|;Niinimäki|Riitta|R|0000-0003-0190-5664;Lähteenmäki|Päivi|P|;Hed Myrberg|Ida|I|0000-0002-8297-2238;Arola|Mikko|M|;Riikonen|Pekka|P|;Lönnqvist|Tuula|T|;Palomäki|Maarit|M|;Ranta|Susanna|S|0000-0001-7854-0371;Harila-Saari|Arja|A|0000-0003-2767-5828;Taskinen|Mervi|M|0000-0002-9907-4725",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27999",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "67(2)",
"journal": "Pediatric blood & cancer",
"keywords": "acute lymphoblastic leukaemia; children; neurotoxicity; outcome; posterior reversible encephalopathy syndrome; sinovenous thrombosis; stroke-like syndrome",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002493:Central Nervous System Diseases; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27999",
"pmc": null,
"pmid": "31674724",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The spectrum of acute central nervous system symptoms during the treatment of childhood acute lymphoblastic leukaemia.",
"title_normalized": "the spectrum of acute central nervous system symptoms during the treatment of childhood acute lymphoblastic leukaemia"
} | [
{
"companynumb": "FI-JAZZ-2020-FI-001563",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPARAGINASE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report the first successful application of in vitro maturation (IVM) of oocytes resulting in live births in two anovulatory women who had suffered oophorectomy following ovarian torsion after stimulation with gonadotropins.\n\n\nMETHODS\nData abstraction was performed from medical records of two subfertile women with excessive functional ovarian reserve. Both women had previously received gonadotropins for ovulation induction or ovarian stimulation, resulting in ovarian torsion. They were offered IVM of oocytes retrieved from antral follicles after mild ovarian stimulation, insemination of mature oocytes using ICSI, and embryo transfer. Outcome measures were the incidence of complications and live birth after fertility treatment.\n\n\nRESULTS\nTransvaginal retrieval of cumulus-oocyte complexes from a unique ovary was conducted. One patient had a singleton live birth after vitrified-warmed embryo transfer in the second IVM cycle. The other patient had a singleton live birth after transfer of a fresh blastocyst in her first IVM cycle.\n\n\nCONCLUSIONS\nAlthough approaches have been developed to prevent ovarian hyperstimulation syndrome (OHSS) and to increase the safety profile of fertility treatment in predicted high responders, women with an excessive functional ovarian reserve may have a non-negligible risk of ovarian torsion. For these patients, IVM should be considered as a safer alternative approach.",
"affiliations": "Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 109, Brussels, Belgium.;Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 109, Brussels, Belgium.;Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 109, Brussels, Belgium.;Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 109, Brussels, Belgium.;Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 109, Brussels, Belgium. michel.devos@uzbrussel.be.",
"authors": "Vesztergom|Dóra|D|;Segers|Ingrid|I|;Mostinckx|Linde|L|;Blockeel|Christophe|C|;De Vos|Michel|M|http://orcid.org/0000-0001-5019-5924",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10815-021-02171-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-0468",
"issue": "38(6)",
"journal": "Journal of assisted reproduction and genetics",
"keywords": "High responder; IVF; IVM; Ovarian stimulation; Ovarian torsion",
"medline_ta": "J Assist Reprod Genet",
"mesh_terms": null,
"nlm_unique_id": "9206495",
"other_id": null,
"pages": "1323-1329",
"pmc": null,
"pmid": "33826051",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "31111879;31347678;19800620;32295778;20814540;32951028;26040479;31399916;30033227;32123754;14645177;29211889;21671163;32974672;26724797;10369209;29534178;19778479;14711538;12410364;30473208;26241855;25302750;22956770;8034085;2295348;18410937;27664204",
"title": "Live births after in vitro maturation of oocytes in women who had suffered adnexal torsion and unilateral oophorectomy following conventional ovarian stimulation.",
"title_normalized": "live births after in vitro maturation of oocytes in women who had suffered adnexal torsion and unilateral oophorectomy following conventional ovarian stimulation"
} | [
{
"companynumb": "BE-ORGANON-O2203BEL001097",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CHORIOGONADOTROPIN ALFA"
},
"drugadditional":... |
{
"abstract": "High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is widely used as a salvage therapy for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL). To investigate the safety and efficacy of regimens including high-dose MCNU followed by ASCT for DLBCL, we analyzed the data from prospective multicenter trials. Twenty-nine patients were analyzed, and the median follow-up time for survival patients was 70 months. Fifteen patients received MCVC conditioning regimen, and fourteen patients received MEAM regimen. Major toxicities associated with these conditioning regimens included nausea (69%), anorexia (66%), febrile neutropenia (62%), diarrhea (59%), and mucositis (34%). One patient who developed severe sinusoidal obstructive syndrome and acute lung injury died without disease progression, and overall therapy-related mortality at 5 years was 3%. No patient developed therapy-related hematological malignancy. At 5 years, overall survival and progression-free survival in all patients were 82.8 and 58.2%, respectively. The 5-year OS in patients treated by the MCVC and MEAM regimens were 73.3 and 92.9%, respectively. These results suggest that regimens including high-dose MCNU followed by ASCT are feasible and effective for the treatment of relapsed or high-risk DLBCL. Further investigation is needed to evaluate of these regimens.",
"affiliations": "Department of Hematology, Nephrology and Rheumatology, Akita University, 44-2 Hasunuma Hiroomote, Akita city, Akita, 010-0041, Japan. ykameoka@doc.med.akita-u.ac.jp.;Department of Hematology, Aomori Prefectural Central Hospital, Aomori, Japan.;Department of Hematology and Oncology, Iwate Medical University, Morioka, Iwate, Japan.;Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.;Department of Hematology, Yamagata University, Yamagata, Japan.;Department of Hematology, Miyagi Cancer Center, Natori, Miyagi, Japan.;Department of Hematology and Oncology, Iwate Medical University, Morioka, Iwate, Japan.;Department of Hematology, Yamagata University, Yamagata, Japan.;Department of Hematology and Oncology, Iwate Medical University, Morioka, Iwate, Japan.;Department of Hemato-pathology, Tohoku University, Sendai, Miyagi, Japan.;Department of Hematology and Rheumatology, Tohoku University, Sendai, Miyagi, Japan.;Department of Hematology, Nephrology and Rheumatology, Akita University, 44-2 Hasunuma Hiroomote, Akita city, Akita, 010-0041, Japan.",
"authors": "Kameoka|Yoshihiro|Y|http://orcid.org/0000-0002-6786-3439;Akagi|Tomoaki|T|;Murai|Kazunori|K|;Noji|Hideyoshi|H|;Kato|Yuichi|Y|;Sasaki|Osamu|O|;Ito|Shigeki|S|;Ishizawa|Kenichi|K|;Ishida|Yoji|Y|;Ichinohasama|Ryo|R|;Harigae|Hideo|H|;Takahashi|Naoto|N|",
"chemical_list": "D009607:Nitrosourea Compounds; C020766:ranimustine",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-018-2508-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "108(5)",
"journal": "International journal of hematology",
"keywords": "ASCT; DLBCL; MCNU",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D064592:Autografts; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009607:Nitrosourea Compounds; D011446:Prospective Studies; D033581:Stem Cell Transplantation; D015996:Survival Rate",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "510-515",
"pmc": null,
"pmid": "30043334",
"pubdate": "2018-11",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": "3043111;17242396;28267593;8673059;24491027;1672260;23054649;8484641;9440722;25546611;20972471;28633038;27365141",
"title": "Safety and efficacy of high-dose ranimustine (MCNU) containing regimen followed by autologous stem cell transplantation for diffuse large B-cell lymphoma.",
"title_normalized": "safety and efficacy of high dose ranimustine mcnu containing regimen followed by autologous stem cell transplantation for diffuse large b cell lymphoma"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1084802",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nExtramedullary disease in multiple myeloma often portends a worse diagnosis. In approximately 1% of cases, multiple myeloma may metastasize to the central nervous system as either leptomeningeal involvement or an intracranial, intraparenchymal lesion. Spinal cord metastases, however, are exceedingly rare. We present a case of spinal cord multiple myeloma as well as a literature review of reported cases.\n\n\nMETHODS\nA 66-year-old African American man with multiple myeloma presented with acute midthoracic pain and lower extremity paresis and paresthesia. Magnetic resonance imaging of the spine revealed two contrast-enhancing intramedullary enhancing lesions in the T1-T2 and T6-T7 cord. Resection with biopsy yielded a diagnosis of metastatic multiple myeloma.\n\n\nCONCLUSIONS\nTo date, only six cases of extramedullary disease to the spinal cord in patients with multiple myeloma have been reported, including our patient's case. In all cases, neurologic deficit was observed at presentation, and magnetic resonance imaging of the spine revealed an intramedullary, homogeneously enhancing lesion. Current evidence suggests worse prognosis in patients with extramedullary disease to the central nervous system, and treatment paradigms remain debatable.",
"affiliations": "Department of Neurosurgery, University of South Florida, Tampa, FL, USA.;Department of Neurosurgery, University of South Florida, Tampa, FL, USA.;Department of Neuro-Oncology, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA.;Department of Neuro-Oncology, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA.;Department of Hematology and Oncology, Moffit Cancer Center, Tampa, FL, USA.;Department of Pathology, Moffit Cancer Center, Tampa, FL, USA.;Department of Neurosurgery, University of South Florida, Tampa, FL, USA. nam.tran@moffitt.org.",
"authors": "Di|Long|L|;Huang|Kevin|K|;Kesayan|Tigran|T|;Kroll|Derek|D|;Baz|Rachid C|RC|;Macaulay|Robert J|RJ|;Tran|Nam D|ND|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-020-02496-5",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n2496\n10.1186/s13256-020-02496-5\nCase Report\nMultiple myeloma presenting as an intramedullary spinal cord tumor: a case report and review of the literature\nDi Long ldi@usf.edu 1 Huang Kevin kevinhuang@usf.edu 1 Kesayan Tigran tigran@usf.edu 23 Kroll Derek derek.kroll@moffitt.org 2 Baz Rachid C. rachid.baz@moffitt.org 4 Macaulay Robert J. robert.macaulay@moffitt.org 5 Tran Nam D. nam.tran@moffitt.org 12 1 grid.170693.a0000 0001 2353 285XDepartment of Neurosurgery, University of South Florida, Tampa, FL USA \n2 grid.468198.a0000 0000 9891 5233Department of Neuro-Oncology, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612 USA \n3 grid.170693.a0000 0001 2353 285XDepartment of Neurology, University of South Florida, Tampa, FL USA \n4 grid.468198.a0000 0000 9891 5233Department of Hematology and Oncology, Moffit Cancer Center, Tampa, FL USA \n5 grid.468198.a0000 0000 9891 5233Department of Pathology, Moffit Cancer Center, Tampa, FL USA \n16 10 2020 \n16 10 2020 \n2020 \n14 1895 6 2020 12 8 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nExtramedullary disease in multiple myeloma often portends a worse diagnosis. In approximately 1% of cases, multiple myeloma may metastasize to the central nervous system as either leptomeningeal involvement or an intracranial, intraparenchymal lesion. Spinal cord metastases, however, are exceedingly rare. We present a case of spinal cord multiple myeloma as well as a literature review of reported cases.\n\nCase presentation\nA 66-year-old African American man with multiple myeloma presented with acute midthoracic pain and lower extremity paresis and paresthesia. Magnetic resonance imaging of the spine revealed two contrast-enhancing intramedullary enhancing lesions in the T1–T2 and T6–T7 cord. Resection with biopsy yielded a diagnosis of metastatic multiple myeloma.\n\nConclusion\nTo date, only six cases of extramedullary disease to the spinal cord in patients with multiple myeloma have been reported, including our patient’s case. In all cases, neurologic deficit was observed at presentation, and magnetic resonance imaging of the spine revealed an intramedullary, homogeneously enhancing lesion. Current evidence suggests worse prognosis in patients with extramedullary disease to the central nervous system, and treatment paradigms remain debatable.\n\nKeywords\nMultiple myelomaIntramedullary spinal cord neoplasmMetastasisSpinal cordCase reportissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nMultiple myeloma (MM) is a hematologic malignancy that accounts for approximately 1.6% of all cancer cases diagnosed in the United States [1]. Extramedullary hematopoietic (EMH) MM, occurring outside of the bone marrow, often portends a poor prognosis and may rarely involve the central nervous system (CNS), causing neurologic deficit, disability, and diminished quality of life [2, 3]. CNS EMH typically presents as an intracranial metastasis that is postulated to arise from hematogenous spread or contiguous seeding from local lytic bone lesions [4, 5]. However, intramedullary spinal cord metastases are exceptionally rare. We present a case of a patient with MM and EMH in the thoracic spinal cord and provide a comprehensive review and discussion of previously reported cases.\n\nCase presentation\nA 66-year-old African American man with relapsed refractory MM and peripheral neuropathy presented to our neurosurgery clinic with a 1-day history of sharp, nonradiating midthoracic back pain and associated numbness and weakness in both legs. He had difficulty ambulating. He had been diagnosed with MM about 3.5 years ago, when he presented with bony pain and imaging revealed lytic bone lesions. His bone marrow biopsy at the time was notable for 70% involvement with MM. Gene expression profiling revealed a high-risk CD-1 subtype, and the result of fluorescence in situ hybridization was notable for t(11;14). He was diagnosed with kappa light chain, International Staging System stage 1, Durie-Salmon stage IIIA MM. Over the past 3.5 years, he had received five prior lines of therapy, including bortezomib, lenalidomide, pomalidomide, carfilzomib, daratumumab, high-dose melphalan, autologous stem cell transplant, and venetoclax. In one of his prior progressive disease events, he was noted to have extramedullary disease with subcutaneous plasmacytomas.\n\nThe patient’s motor examination revealed 4/5 strength in hip flexion and knee extension bilaterally. His patellar and Achilles deep tendons reflexes were 1+ bilaterally. His sensation to light touch was intact but subjectively decreased in a patchy distribution below the T5–T6 dermatome. On the basis of these findings, magnetic resonance imaging (MRI) of the thoracic spine was performed, which revealed two contrast-enhancing intramedullary lesions, with the largest at the T2–T3 level and a smaller lesion at T6–T7 (Fig. 1a–c). The result of MRI of the brain with and without contrast was unremarkable.\nFig. 1 a–c Post-contrast sagittal T1-WI (T1-WI + contrast), T2-WI STIR, and axial T1-WI + contrast images showing intramedullary metastatic lesion (red arrows). Sagittal sequences show a dramatically enhancing lesion at the T2–T3 vertebral level and a second enhancing lesion in the dorsal cord at T6–T7. Axial sequences confirm the presence of the T2–T3 intramedullary spinal cord lesion. d–f Post-operative sequences showing complete resection of the T2–T3 lesion (red arrow). Expected post-surgical changes are seen with associated spinal cord edema. The T6–T7 lesion was not resected and remains identifiable on T1-WI + contrast magnetic resonance image. STIR short tau inversion recovery, WI weighted image\n\n\n\nA working diagnosis of a neoplastic process was made. Given the rarity of MM with CNS metastasis, a biopsy for pathologic analysis was recommended. The patient underwent a thoracic T2–T3 laminectomy and intradural exploration. The spinal cord appeared mildly expanded. Ultrasound was used to localize the intramedullary tumor. Using standard microsurgical technique, a midline myelotomy was performed and immediately revealed a tan, well-circumscribed mass. The tumor was circumferentially mobilized, and complete tumor resection was performed (Fig. 1d–f).\n\nThe histological diagnosis yielded metastatic MM with high cellularity, amphophilic cytoplasm, rounded cell borders, and irregular pleomorphic nuclei. The myeloid component was demarcated from CNS tissue consistent with spinal cord. Numerous mitotic figures were observed, up to seven per high-power field. The neoplastic cells were immunoreactive for CD138 with only scattered overexpression of p53 interpreted as physiological upregulation. The patient’s Ki67 index was 75%. In situ hybridization revealed strong positive expression of kappa light chain with minimal lambda staining.\n\nPostoperatively, the patient’s motor function improved from his preoperative baseline with mild worsening of proprioception. His neurologic examination result remained stable at 3 months. He completed fractionated stereotactic radiosurgery with 2 Gy in eight fractions.\n\nDiscussion\nWe present a case of a patient with MM and EMH with metastasis to the thoracic spinal cord causing intramedullary disease. In addition, we conducted a literature review of all reported cases of MM or plasmacytoma with spinal cord metastasis. The results are summarized in Table 1. Including our patient’s case, there exist only six reported cases, four diagnosed as MM and two diagnosed as plasmacytoma. Five of the six patients were male (83.3%), and one patient was female (16.67%). Mean age at presentation was 51.2 years old. The most common presenting neurologic deficit was muscle weakness, which occurred in four of six cases (66.7%), followed by paresthesia in two of six cases (33.3%). In all cases, lesions were contrast-enhancing on either T1- or T2-weighted MRI sequences.\nTable 1 Clinical results of multiple myeloma or plasmacytoma metastasizing to the spinal cord in the literature\n\nStudy\tYear\tAge (years)\tSex\tDiagnosis\tNeurologic deficits\tTumor location\tMRI features\tTreatment\tOverall survival (months)\t\nDi et al.\t2019\t66\tM\tMultiple myeloma\tLower extremity paresthesia and weakness, gait difficulty\tT2–T3, T6–T7\tT1 w/contrast: enhancing intramedullary mass with prominent associated spinal cord edema\tSurgery + RT\tN/A\t\nVarettoni et al.\t2008\t56\tM\tMultiple myeloma\tWeakness, paraparesis\tThoracic (T1–T2, T5–T6) and lumbar (L2–L3)\tT1-weighted: progression of bone lesions, paraspinal plasmacytoma, and diffuse infiltration of the spinal cord\tChemo-RT\t1.4\t\nHans et al.\t2013\t52\tM\tPlasmacytoma\tParesthesia, sensory deficit, progressive tetraparesis\tC5–C6\tT1/T2 showed mild enlargement of the cord with slight signal intensity from C5–C6. T2 w/contrast enhancement showed small, irregular area of “mild to moderate nodular homogeneous contrast enhancement” at ventral periphery of C5\tChemo-RT\tNot reported, but describes significant neurologic deterioration at 10 months\t\nVale et al.\t2012\t51\tM\tMultiple myeloma\tWeakness and paresis of left lower extremity\tL1–cauda equina\tSagittal T2 w/contrast showed diffuse infiltration of the cauda equina, extending from L1 to L4. Axial T2 w/contrast showed enhancement of roots at L3 level.\tChemo-RT\t11\t\nTouzeau et al.\t2004\t51\tF\tMultiple myeloma\tProgressive ataxia\tMultiple lesions from C2 to T6\tN/A\tChemo-RT\t6.75\t\nGao et al.\t2007\t31\tM\tPlasmacytoma\tProgressive lower extremity weakness and abasia. Bilateral abdominal, cremasteric, patellar tendon,and Achilles tendon reflexes absent\tT7–T8\tT1-weighted: extensive homogeneous isointense signal T6–T10T2-weighted: high-signal T6–T10T1 w/contrast: enhancing irregular lesion in anterior portion of T7–T8Chest, thoracic, and lumbar spine normal on MRI\tSurgery\tNot reported\t\nAbbreviations: MRI magnetic resonance imaging, N/A not applicable, RT radiotherapy\n\n\n\nDifferential diagnosis of MM\nDiagnosing MM often requires the evaluation of clinical, radiographic, histopathologic, and laboratory findings [6–8]. In symptomatic patients, metastasis to the axial skeleton most often presents with back pain, vertebral fractures, or paresthesia and paresis due to spinal cord compression [9]. Lytic bone lesions may result in hypercalcemia, and renal dysfunction may present as anemia and proteinuria [10]. The differential diagnosis of MM may include monoclonal gammopathy of uncertain significance, Waldenstrom macroglobulinemia, and other plasma cell dyscrasias. The CRAB acronym (calcium elevation, renal dysfunction, anemia, and bone disease) was established by the International Myeloma Working Group to summarize the aforementioned clinical manifestations of MM as well as to differentiate between MM and similar plasma cell dyscrasias such as solitary plasmacytoma [11]. Differentiating MM from solitary plasmacytoma involves review of radiographic imaging and bone marrow biopsy [1]. Both dyscrasias require biopsy of bone lesions with evidence of clonal plasma cells. However, in solitary plasmacytoma, the CRAB symptoms are absent; there is no evidence of clonal plasma cells on bone marrow biopsy; and radiographic imaging reveals no other abnormalities aside from the primary lesion.\n\nEMH disease in MM\nEMH is relatively uncommon at diagnosis but may occur later in the disease progression or at the time of relapse. Incidence of EMH in newly diagnosed MM is approximately 7–18% [12–14]. This proportion increases to 6–20% late in the disease course [13–16]. Several studies have shown that patients with EMH at presentation have significantly shorter survival with conventional chemotherapy [2, 12, 13]. In addition, Pour et al. described significantly worse outcomes in patients with soft tissue–related EMH than in bone-related EMH, with median survival rates of 5 months and 12 months, respectively (P = 0.022) [2]. Median survival of patients with CNS EMH shows similarly poor outcomes, with most studies reporting median survival of 2–8 months [3, 4, 17–22]. However, several of these studies included only intracranial metastases, and the others did not specify location further than detailing CNS involvement. Due to the extreme rarity of EMH involving the spinal cord, it is difficult to determine whether patient survival may differ from intracranial involvement. In consideration of the small sample size, we report an overall survival of 1–11 months on the basis of our literature review.\n\nMM in the CNS\nInvolvement of the CNS is relatively uncommon, with approximately 1–2% of patients with MM exhibiting a secondary CNS malignancy [23, 24]. Most often, these occur as either an intraparenchymal or meningeal lesion. MM metastasis to the spinal cord is exceedingly rare. Our review returned a total of six reported patients with metastatic, intramedullary spinal cord MM or plasmacytoma in the past 15 years, including our patient’s case. Five patients were male (83.3%), and one patient was female (16.7%). Two cases had a final diagnosis of plasmacytoma (33.3%), and four had a diagnosis of MM (66.7%). Bence-Jones proteinuria was reported in two cases (33.3%). The level of spinal cord metastasis varied from the cervical cord to the cauda equina.\n\nDiagnosis of MM in the CNS often involves contrast-enhanced MRI of the head and/or spine. It should be noted that there remains concern for the use of iodine-based contrast agents in MM and monoclonal gammopathies [25]. Many radiologists consider the use of iodinated contrast material to be contraindicated in the setting of MM due to impaired renal function. Following administration of gadolinium contrast, MM may present as diffuse leptomeningeal enhancement or punctate, intraparenchymal lesions [26]. MM of the spinal cord shares similar characteristics. In all cases in which radiologic findings were reported, contrast-enhanced T1 weighted image (T1-WI) MRI of the spine showed a contrast-enhancing lesion; these lesions can present diffusely, with multiple enhancing lesions spread across spinal levels.\n\nPathogenesis of CNS EMH\nSeveral theories have been posited to suggest how CNS involvement in MM may arise. Local paraskeletal seeding of meninges and subsequent invasion into neural tissue has been suggested. Gozzetti et al. found neuroimaging evidence of contiguous spread arising directly from adjacent bone lesions [4]. Another hypothesis suggests hematogenous spread from traversal of the arachnoid veins by myeloma cells [5]. Spillage of cells into the cerebrospinal fluid would thus then be evident on cytologic assessment [20]. In this way, the neural invasion of MM closely reflects that seen in acute lymphoblastic leukemia, in which CNS involvement initially involves the adventitia bordering the arachnoid veins [27]. Few studies have investigated the molecular basis of CNS myeloma, but the acquisition of p53 gene mutations seems to be associated with advanced forms of disease [28, 29]. In a sample of nine patients, Chang et al. identified an 89% rate of p53 deletions, which stands in stark contrast to 10–15% of patients with MM who harbor p53 deletions but do not have CNS involvement [29]. In our patient’s case, immunostaining revealed only scattered p53 overexpression, suggestive of physiological upregulation rather than a gene mutation. Multiple lytic and lucent osseous lesions throughout the spinal axis were identified, notably in the thoracic spine. These were attributed to either multiple osseous degenerative changes or multifocal myelomatous disease. Thus, it is possible that the intramedullary disease in our patient arose from contiguous spread from nearby bone lesions. However, the presence of the second T6–T7 lesion located dorsally along the cord favors hematogenous spread from penetrating branches of the posterior spinal arteries, because contiguous spread throughout the width of the spinal cord from a vertebral lesion seems less likely.\n\nTreatment paradigms for CNS MM\nTreatment of CNS MM is not well defined; however, some studies have suggested systemic therapy, occasionally with adjuvant radiation [20]. Systemic strategies present challenges because the blood–brain barrier (BBB) precludes treatment with traditional chemotherapeutics, such as high-dose melphalan, cyclophosphamide, proteasome inhibitors, or monoclonal antibodies. High-dose methotrexate or cytarabine is effective in penetrating the CNS but is ineffective against MM [30]. Thus, effective therapy necessitates good BBB permeability as well as action against MM. Thalidomide, lenalidomide, and pomalidomide have been shown to traverse the BBB in primates [31], and combination thalidomide and bendamustine has been shown to achieve a robust effect [32]. Of course, its use has yet to be validated in large-sample studies. More recently, selinexor was approved for patients with advanced MM, and this agent seems to cross the BBB. Combination BRAF and mitogen-activated protein kinase kinase 1/2 inhibitors dabrafenib/trametinib have also been employed to good response; however, recent evidence suggests potential mechanisms of drug resistance [33]. Given the reported radiosensitivity of plasma cell dyscrasias, concurrent radiotherapy may be considered [4, 34, 35]. Ultimately, intrathecal chemotherapy with a systemic anti-MM immunomodulatory regimen and cranial and/or spinal irradiation seems an ideal approach to management [21, 30]. Of six patients in our review, three patients (50%) were treated with chemoradiation therapy (chemo-RT); two patients (33.3%), including our own, underwent resection with adjuvant chemo-RT; and one patient (16.7%) underwent biopsy with chemo-RT.\n\nAll patients treated with chemo-RT saw progression in paresis and other neurological deficits over the course of treatment. Reported overall survival ranges from 1.4 to 11 months among patients treated with chemo-RT only. The role of surgery in intracranial EMH is unclear, and resection is not frequently performed [20]. However, in spinal cord metastasis, resection may assume a more prominent role because mass effect from intramedullary lesions may perturb motor and sensory tracts and compress nerve roots, contributing to radiculopathies. We found no data for patients treated with resection and chemo-RT. Hans et al. noted that surgical excision should be considered whenever possible. However, it is difficult to interpret the effect of surgery on patient morbidity and mortality, given the paucity of data. Our patient did not experience any perioperative complications, but the long-term effect of surgery on disease progression has yet to be observed.\n\nConclusion\nIntramedullary spinal cord metastasis is exceedingly rare and may present as paresthesia and myelopathy in patients with a history of MM. Intramedullary metastases appear as moderately contrast-enhancing lesions on T1-weighted images, often with diffuse infiltration across multiple spinal levels. Surgical debulking should be considered to alleviate mass effect on white matter tracts and nerve root compression. Radiotherapy with systemic therapy that ideally has BBB penetration remains a mainstay of treatment for managing this complicated stage of disease.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nLD assisted with data acquisition, figure and table generation, manuscript preparation, and review. KH and TK assisted with manuscript preparation and review. All authors read and approved the final manuscript.\n\nFunding\nThe authors have no funding sources to declare.\n\nAvailability of data and materials\nThe de-identified patient information presented in this report is available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThis case report did not constitute human subjects research, and thus institutional review board approval was not sought or required. All patient information was de-identified in accordance with Health Insurance Portability and Accountability Act guidelines.\n\nConsent for publication\nWe affirm that the material in this report has not been published and is not being considered for publication elsewhere, either in whole or in part. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1. Michels TC Petersen KE Multiple myeloma: diagnosis and treatment Am Fam Physician 2017 95 6 373 383 28318212 \n2. Pour L Sevcikova S Greslikova H Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse Haematologica 2014 99 2 360 364 10.3324/haematol.2013.094409 24038024 \n3. Schluterman KO Fassas AB Van Hemert RL Harik SI Multiple myeloma invasion of the central nervous system Arch Neurol 2004 61 9 1423 1429 10.1001/archneur.61.9.1423 15364689 \n4. Gozzetti A Cerase A Lotti F Extramedullary intracranial localization of multiple myeloma and treatment with novel agents: a retrospective survey of 50 patients Cancer 2012 118 6 1574 1584 10.1002/cncr.26447 21932386 \n5. Truong LD Kim HS Estrada R Meningeal myeloma Am J Clin Pathol 1982 78 4 532 535 10.1093/ajcp/78.4.532 7137086 \n6. Rollig C Knop S Bornhauser M Multiple myeloma Lancet 2015 385 9983 2197 2208 10.1016/S0140-6736(14)60493-1 25540889 \n7. Bird JM Owen RG D’Sa S Guidelines for the diagnosis and management of multiple myeloma 2011 Br J Haematol 2011 154 1 32 75 10.1111/j.1365-2141.2011.08573.x 21569004 \n8. Moreau P San Miguel J Sonneveld P Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2017 28 Suppl 4 iv52 iv61 10.1093/annonc/mdx096 \n9. Kyle RA Gertz MA Witzig TE Review of 1027 patients with newly diagnosed multiple myeloma Mayo Clin Proc 2003 78 1 21 33 10.4065/78.1.21 12528874 \n10. Riccardi A Gobbi PG Ucci G Changing clinical presentation of multiple myeloma Eur J Cancer 1991 27 11 1401 1405 10.1016/0277-5379(91)90020-E 1835856 \n11. Nakaya A Fujita S Satake A Impact of CRAB symptoms in survival of patients with symptomatic myeloma in novel agent era Hematol Rep 2017 9 1 6887 10.4081/hr.2017.6887 28286629 \n12. Varettoni M Corso A Pica G Mangiacavalli S Pascutto C Lazzarino M Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients Ann Oncol 2010 21 2 325 330 10.1093/annonc/mdp329 19633044 \n13. Wu P Davies FE Boyd K The impact of extramedullary disease at presentation on the outcome of myeloma Leuk Lymphoma 2009 50 2 230 235 10.1080/10428190802657751 19197724 \n14. Blade J Lust JA Kyle RA Immunoglobulin D multiple myeloma: presenting features, response to therapy, and survival in a series of 53 cases J Clin Oncol 1994 12 11 2398 2404 10.1200/JCO.1994.12.11.2398 7964956 \n15. Rajkumar SV Dispenzieri A Lacy MQ Incidence and survival outcomes of extramedullary myeloma [abstract] Blood 2013 122 21 3141 \n16. Blade J Kyle RA Greipp PR Presenting features and prognosis in 72 patients with multiple myeloma who were younger than 40 years Br J Haematol 1996 93 2 345 351 10.1046/j.1365-2141.1996.5191061.x 8639427 \n17. Majd N Demopoulos A Chari A Central nervous system involvement in multiple myeloma patients in the era of novel therapies [abstract P07.005] Neurology 2013 80 7 Suppl P07.005 \n18. Dias A Higashi F Peres ALM Cury P Crusoe EQ Hungria VTM Multiple myeloma and central nervous system involvement: experience of a Brazilian center Rev Bras Hematol Hemoter 2018 40 1 30 36 29519370 \n19. Paludo J Painuly U Kumar S Myelomatous involvement of the central nervous system Clin Lymphoma Myeloma Leuk 2016 16 11 644 654 10.1016/j.clml.2016.08.010 27624224 \n20. Jurczyszyn A Grzasko N Gozzetti A Central nervous system involvement by multiple myeloma: a multi-institutional retrospective study of 172 patients in daily clinical practice Am J Hematol 2016 91 6 575 580 10.1002/ajh.24351 26955792 \n21. Chen CI Masih-Khan E Jiang H Central nervous system involvement with multiple myeloma: long term survival can be achieved with radiation, intrathecal chemotherapy, and immunomodulatory agents Br J Haematol 2013 162 4 483 488 10.1111/bjh.12414 23772701 \n22. Abdallah AO Atrash S Shahid Z Patterns of central nervous system involvement in relapsed and refractory multiple myeloma Clin Lymphoma Myeloma Leuk 2014 14 3 211 214 10.1016/j.clml.2013.11.004 24373936 \n23. Fassas AB Muwalla F Berryman T Myeloma of the central nervous system: association with high-risk chromosomal abnormalities, plasmablastic morphology and extramedullary manifestations Br J Haematol 2002 117 1 103 108 10.1046/j.1365-2141.2002.03401.x 11918539 \n24. Qu XY Fu WJ Xi H Zhou F Wei W Hou J Clinical features of multiple myeloma invasion of the central nervous system in Chinese patients Chin Med J 2010 123 11 1402 1406 20819595 \n25. Stacul F Bertolotto M Thomsen HS Iodine-based contrast media, multiple myeloma and monoclonal gammopathies: literature review and ESUR Contrast Media Safety Committee guidelines Eur Radiol 2018 28 2 683 691 10.1007/s00330-017-5023-5 28856420 \n26. Leifer D Grabowski T Simonian N Demirjian ZN Leptomeningeal myelomatosis presenting with mental status changes and other neurologic findings Cancer 1992 70 7 1899 1904 10.1002/1097-0142(19921001)70:7<1899::AID-CNCR2820700716>3.0.CO;2-3 1525764 \n27. Price RA Johnson WW The central nervous system in childhood leukemia. I. The arachnoid Cancer 1973 31 3 520 533 10.1002/1097-0142(197303)31:3<520::AID-CNCR2820310306>3.0.CO;2-2 4511909 \n28. Neri A Baldini L Trecca D Cro L Polli E Maiolo AT p53 gene mutations in multiple myeloma are associated with advanced forms of malignancy Blood 1993 81 1 128 135 10.1182/blood.V81.1.128.128 8417784 \n29. Chang H Sloan S Li D Keith Stewart A Multiple myeloma involving central nervous system: high frequency of chromosome 17p13.1 (p53) deletions Br J Haematol 2004 127 3 280 284 10.1111/j.1365-2141.2004.05199.x 15491286 \n30. Touzeau C Moreau P How I treat extramedullary myeloma Blood 2016 127 8 971 976 10.1182/blood-2015-07-635383 26679866 \n31. Muscal JA Sun Y Nuchtern JG Plasma and cerebrospinal fluid pharmacokinetics of thalidomide and lenalidomide in nonhuman primates Cancer Chemother Pharmacol 2012 69 4 943 947 10.1007/s00280-011-1781-y 22109830 \n32. Nahi H Svedmyr E Lerner R Bendamustine in combination with high-dose radiotherapy and thalidomide is effective in treatment of multiple myeloma with central nervous system involvement Eur J Haematol 2014 92 5 454 455 10.1111/ejh.12247 24330308 \n33. Da Via MC Solimando AG CIC-mutation as a potential molecular mechanism of acquired resistance to combined BRAF/MEK inhibition in CNS multiple myeloma [abstract] Blood 2018 132 Suppl 1 3181 10.1182/blood-2018-99-117203 \n34. Petersen SL Wagner A Gimsing P Cerebral and meningeal multiple myeloma after autologous stem cell transplantation: a case report and review of the literature Am J Hematol 1999 62 4 228 233 10.1002/(SICI)1096-8652(199912)62:4<228::AID-AJH5>3.0.CO;2-3 10589078 \n35. Gangatharan SA Carney DA Prince HM Emergence of central nervous system myeloma in the era of novel agents Hematol Oncol 2012 30 4 170 174 10.1002/hon.1021 22144117\n\n",
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"keywords": "Case report; Intramedullary spinal cord neoplasm; Metastasis; Multiple myeloma; Spinal cord",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009101:Multiple Myeloma; D013116:Spinal Cord; D013120:Spinal Cord Neoplasms",
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"title": "Multiple myeloma presenting as an intramedullary spinal cord tumor: a case report and review of the literature.",
"title_normalized": "multiple myeloma presenting as an intramedullary spinal cord tumor a case report and review of the literature"
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"abstract": "BACKGROUND\nAlthough risk factors for torsade de pointes (TdP) are known, identifying hospitalized patients at greatest risk for QTcP who should receive cardiac monitoring is poorly defined.\n\n\nOBJECTIVE\nDescribe the prevalence of risk for TdP in patients and associations between risk factors and QTc prolongation (QTcP) at a tertiary teaching hospital.\n\n\nMETHODS\nThis retrospective analysis assessed physiological and pharmacological risk factors for TdP of adult patients receiving ≥1 QTc-prolonging medications (QTcMed) during hospitalization. The QTcMeds were stratified by risk for causing TdP (probable, possible, and conditional). Baseline electrocardiograms (ECGs) were assessed for QTcP associated with risk for TdP.\n\n\nRESULTS\nDuring a 6-month period, 12,401 (51%) hospitalizations received ≥1 QTcMed. A baseline ECG was obtained for 2381 (19%) patients. A total of 386 (16%) patients with a baseline ECG were found to have QTcP. Significant associations for QTcP were found with the following physiological risk factors: female (P = .021), left-ventricular ejection fraction <40% (P < .0001), cardiac arrest (P < .0001), and cardioversion (P = .007). Significantly more patients with QTcP (n = 209, 54%) received probable-risk QTcMeds than those without QTcP (n = 542, 27%; P < .0001). Probable-risk QTcMeds administered alone or concomitantly with other QTcMeds were more frequently associated with QTcP. No documented cases of TdP were identified.\n\n\nCONCLUSIONS\nOf the population receiving QTcMeds, only a small portion had a baseline ECG, identifying a large population at risk of QTcP without appropriate monitoring. Patients with cardiac disease receiving probable-risk QTcMeds were associated with the highest risk of QTcP and should be monitored closely.",
"affiliations": "St Luke's Health System, Houston, TX, USA.",
"authors": "Jardin|Carla G M|CG|;Putney|David|D|;Michaud|Stephen|S|",
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"keywords": "QTc prolongation; electrocardiogram; pharmacological risk factor; physiological risk factor; torsade de pointes",
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"mesh_terms": "D000328:Adult; D000368:Aged; D004562:Electrocardiography; D005260:Female; D006323:Heart Arrest; D006760:Hospitalization; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D016171:Torsades de Pointes; D016277:Ventricular Function, Left",
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"title": "Assessment of drug-induced torsade de pointes risk for hospitalized high-risk patients receiving QT-prolonging agents.",
"title_normalized": "assessment of drug induced torsade de pointes risk for hospitalized high risk patients receiving qt prolonging agents"
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"abstract": "Treatment strategies of back pain are variable. We describe an unusual case of polyuria and erectile dysfunction with a short-term tramadol use. A 29-year-old man presented to our clinic with worsening lower back pain. After poor control of his pain on Non steroidal anti-inflammatory drugs, tramadol was prescribed. After 3 days of starting tramadol, he experienced significant polyuria and erectile dysfunction with inability to ejaculate or obtain orgasm. He denied any systemic symptoms. On follow-up, he reported complete resolution of his polyuria and erectile dysfunction within 24 h of stopping tramadol, in addition to satisfactory control of his pain. Polyuria and erectile dysfunction are very uncommon side effects of tramadol, reported in <1% of chronic users. This is the first case report to demonstrate such a rapid and aggressive onset of this combination of rare side effects with the complete resolution after tramadol discontinuation.",
"affiliations": "Advocate Illinois Masonic Medical Center , Chicago, IL , USA.;Chicago Medical School , Chicago, IL , USA.",
"authors": "Hassan|Abdalla|A|;Chen|Cindy|C|",
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"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcromcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omv060omv0601800Case ReportsPain management in our daily practice: should we re-evaluate? Hassan Abdalla 1*Chen Cindy 21 Advocate Illinois Masonic Medical Center, Chicago, IL, USA2 Chicago Medical School, Chicago, IL, USA* Correspondence address. Internal Medicine Department, 7th floor, Advocate Illinois Masonic Medical Center, 836 W Wellington Ave., Chicago, IL 60657, USA. Tel: +773-296-7046; Fax: +773-296-7486; E-mail: abdalla.hassan@advocatehealth.com11 2015 03 11 2015 2015 11 349 350 23 3 2015 12 9 2015 30 9 2015 © The Author 2015. Published by Oxford University Press.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comTreatment strategies of back pain are variable. We describe an unusual case of polyuria and erectile dysfunction with a short-term tramadol use. A 29-year-old man presented to our clinic with worsening lower back pain. After poor control of his pain on Non steroidal anti-inflammatory drugs, tramadol was prescribed. After 3 days of starting tramadol, he experienced significant polyuria and erectile dysfunction with inability to ejaculate or obtain orgasm. He denied any systemic symptoms. On follow-up, he reported complete resolution of his polyuria and erectile dysfunction within 24 h of stopping tramadol, in addition to satisfactory control of his pain. Polyuria and erectile dysfunction are very uncommon side effects of tramadol, reported in <1% of chronic users. This is the first case report to demonstrate such a rapid and aggressive onset of this combination of rare side effects with the complete resolution after tramadol discontinuation.\n==== Body\nINTRODUCTION\nLow back pain is a very common problem in the general population, affecting as many as 84% of adults in their lifetimes [1]. While the overall long-term prognosis of low back pain is favorable, the symptoms can be persistent and severe, leading to significant impacts on patient lifestyles and quality of life. There are a variety of treatment strategies that include pharmacologic and nonpharmacologic interventions. For most patients, first-line pharmacologic agents include acetaminophen or nonsteroidal anti-inflammatory drugs; time-limited courses of opioids may be considered for debilitating pain that is not controlled with acetaminophen or NSAIDs [2]. Tramadol is an analgesic with some activity at μ-opioid receptors, in addition to inhibition of serotonin and norepinephrine uptake. Side effects of tramadol most commonly include gastrointestinal disturbances such as constipation, nausea and vomiting, as well as dizziness and somnolence [3]. In this report, we describe a very unusual case of marked urinary symptoms and erectile dysfunction in association with a short-term course of tramadol.\n\nCASE REPORT\nA 29-year-old man with no significant past medical history presented to our outpatient clinic with worsening intermittent sharp or burning pain and occasional numbness in his left buttock shooting down into the posterior thigh. The symptoms were infrequent and mild when they first started 2 years ago, but his symptoms had become more severe over the past 6 months, interfering with his sleep and studies as a graduate student. He denied any history of bowel or bladder incontinence, saddle anesthesia or history trauma to his spine. He denied any systemic or urinary symptoms. His physical examination was significant for tenderness at L5 vertebra and sacrum, pain and limited range of motion with lumbar flexion, a positive left straight leg raise test. His presentation was consistent with sciatica and he has a BMI of 35 kg/m2. Accordingly, he was counseled about proper diet and exercise, and ibuprofen 800 mg TID for a week was prescribed with gabapentin 300 mg daily at bedtime if he had no improvement with ibuprofen alone. He was also referred for physical therapy. X-ray imaging of the lumbar spine and of the bilateral hips and pelvis showed partial sacralization of the L5 vertebrae and minimal retrolisthesis of L4 with respect to L5. There was no evidence of fracture, dislocation or diatheses of the pelvis or hips.\n\nOn follow-up of 3 weeks later, he reported minimal improvement with ibuprofen and gabapentin. He had not yet commenced physical therapy at that time. His gabapentin dose was changed to 300 mg in the morning and 600 mg at bedtime, and an MRI of the lumbar spine was done and it showed a 5-mm central posterior protrusion of the L4–L5 disc without significant dural sac or nerve root compression, mild left foraminal stenosis at the L4–L5 level and a markedly degenerated and hypoplastic L5–S1 disc with sacralization of the L5 vertebra bilaterally. He returned to the office after 4 days in order to follow-up on the MRI results and for further pain management, stating that the increase in gabapentin helped the sciatica to some degree, but he was continuing to have significant lower back pain. At that time, he was started on tramadol 50 mg TID as needed for pain, in addition to ibuprofen and gabapentin.\n\nThe patient returned to the office 3 days after starting tramadol. He reported that his lower back pain had been completely resolved with tramadol, but after the second dose of tramadol, he was experiencing increased urinary frequency. He recalled needing to urinate at least 15 times in a 24-h period, including 9 or 10 times at night. He also noted erectile dysfunction, with the absence of morning erections, inability to maintain an erection and inability to ejaculate or obtain orgasm. He denied dysuria or any systemic symptoms and reported having the same fluid intake. His urine analysis was normal. Based on these findings and the apparent cause–effect relationship, tramadol was stopped and he was prescribed Norco every 6 h as needed for pain for 10 days until he could start physical therapy.\n\nTwo weeks later, the patient came for follow-up. His pain was well controlled on Norco, and he had complete resolution of his urinary and erectile dysfunction within 24 h of stopping tramadol. He was scheduled to start physical therapy the following week and he is doing very well now.\n\nDISCUSSION\nBoth polyuria and erectile dysfunction are very uncommon side effects of tramadol, reported in <1% of people taking the drug [4–6]. The effects of tramadol on sexual dysfunction are relatively expected despite the apparent rarity of the side effect, as it has been used in various studies for the treatment of premature ejaculation [7, 8]. Tramadol is an analgesic with centrally acting opioid activity (weak μ-opioid effect) in addition to inhibition of reuptake of 5-hydroxytryptamine and norepinephrine. It is hypothesized that the increased synaptic content of serotonin and norepinephrine at the level of the spinal cord and peripheral sensory nerves provides the mechanism for these side effects as well as for effective treatment of premature ejaculation. A prove to this hypothesis is that tramadol is being used more often in the treatment on premature ejaculation as an off-label use. Urinary dysfunction, though it has been reported to the FDA, is less common than erectile dysfunction. Out of 38 627 people who reported side effects while taking tramadol, the majority of those reporting urinary frequency (63%) or polyuria (100%) had been taking tramadol for at least 2 years, with only 2 of the 38 627 reporting urinary frequency within 1 month of taking tramadol [4, 5]. Gender distribution was equal in those experiencing urinary frequency, but predominantly female in those experiencing polyuria. Patients reporting these side effects tended to be older than age 50 years. The large majority had no resolution of symptoms with discontinuation of the medication. Of note, tramadol has been successfully tried as a treatment for overactive bladder [9]. The mechanism of tramadol-induced polyuria is not completely understood and contradicts the abovementioned proposed mechanism of action, since despite having some possible anticholinergic effects (tricyclic antidepressant-like effect) and the fact that it has been successfully tried as a treatment for overactive bladder, it is not clear how tramadol can cause polyuria instead of urine retention.\n\nThis case was very unique and interesting for its presentation of polyuria and erectile dysfunction in a relatively young healthy male. Moreover, we believe that this is the first case report to demonstrate such a rapid and aggressive onset of this combination of rare side effects as well as the complete resolution of the symptoms within 24 h of tramadol discontinuation.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n==== Refs\nREFERENCES\n1 Cassidy JD , Carroll LJ , Côté P \nThe Saskatchewan health and back pain survey. The prevalence of low back pain and related disability in Saskatchewan adults . Spine \n1998 ;23 :1860 .9762743 \n2 Chou R , Qaseem A , Snow V , Casey D , Cross JT Jr, Shekelle P et al \nDiagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society . Ann Intern Med \n2007 ;147 :478 .17909209 \n3 Mercier F , Claret L , Prins K , Bruno R \nA model-based meta-analysis to compare efficacy and tolerability of tramadol and tapentadol for the treatment of chronic non-malignant pain . Pain Ther \n2014 ;3 :31 –44 .25135386 \n4 Safarinejad MR , Hosseini SY \nSafety and efficacy of tramadol in the treatment of premature ejaculation: a double-blind, placebo-controlled, fixed-dose, randomized study . J Clin Psychopharmacol \n2006 ;26 :27 –31 .16415702 \n5 Yang L , Qian S , Liu H , Liu L , Pu C , Han P et al \nRole of tramadol in premature ejaculation: a systematic review and meta-analysis . Urol Int \n2013 ;91 :197 –205 .23751284 \n6 Safarinejad MR , Hosseini SY \nSafety and efficacy of tramadol in the treatment of idiopathic detrusor overactivity: a double-blind, placebo-controlled, randomized study . Br J Clin Pharmacol \n2006 ;61 :456 –63 .16542207 \n7 Err H , Wiwanitkit V \nTramadol and sexual dysfunction . Indian J Psychol Med \n2015 ;37 :107 .25722526 \n8 McMahon CG , Porst H \nOral agents for the treatment of premature ejaculation: review of efficacy and safety in the context of the recent International Society for Sexual Medicine criteria for lifelong premature ejaculation . J Sex Med \n2011 ;8 :2707 –25 .21771283 \n9 Sansone RA , Sansone LA \nTramadol: seizures, serotonin syndrome, and coadministered antidepressants . Psychiatry (Edgmont) \n2009 ;6 :17 –21 .19724727\n\n",
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"abstract": "There are few reports of using oxaliplatin(L-OHP)for esophageal squamous cell carcinoma.We report a case of long-term disease control after administration of L-OHP for esophagogastric junction squamous cell carcinoma(EG).A woman in her 40s was diagnosed with EG(cT3, cN2, cM0, cStage Ⅲ).She received thoracoscopic, laparoscopic-assisted, subtotal esophagectomy with 3-field dissection after 3 courses of preoperative chemotherapy with DCF(docetaxel hydrate, cisplatin, 5- fluorouracil).Reconstruction was achieved using a retrosternally shifted gastric tube and transesophageal gastro-tubing. Pathological examination showed EG(ypT3, ypN2, ypM0, ypStage Ⅲ)(chemotherapy evaluation: Grade 1a).After 12 months, para-aortic lymph node recurrence(#112aoP, #16a2lat)was observed on a follow-up CT examination.First, we administered 5 courses of chemotherapy with SOX(S-1 100mg/m2 day 1-14 and L-OHP 100 mg/m2 day 1).Recurrent lymph nodes shrunk slightly, and there were no new lesions.Subsequently, there was no other adverse event except for Grade 1 chemotherapy-induced neuropathy.Second, we administered 3 courses of chemotherapy with FOLFOX(5-FU 400mg/m2, L-OHP 85mg/m2, Leucovorin 200 mg/m2 day 1, 5-FU 1,600mg/m2/46 hr)in combination with radiotherapy(total 60 Gy/ 30 Fr).Recurrent lymph nodes shrunk slightly, and there were no new lesions.Subsequently, there was no other adverse event except for Grade 1 chemotherapy-induced neuropathy.No new recurrence was observed 19 months after the first recur- rence.The patient continues to receive weekly nab-PTX(85mg/m2).A regimen that includes L-OHP is useful in the treatment of advanced or recurrent esophageal squamous cell carcinoma.",
"affiliations": "Dept. of Gastroenterological Surgery, Osaka General Medical Center.",
"authors": "Minami|Soichiro|S|;Motoori|Masaaki|M|;Miyazaki|Yasuhiro|Y|;Nishizawa|Yujiro|Y|;Komatsu|Hisateru|H|;Inoue|Akira|A|;Tomokuni|Akira|A|;Komori|Takamichi|T|;Fujitani|Kazumasa|K|;Iwase|Kazuhiro|K|",
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"title": "A Case of Long-Term Disease Control after Administration of Oxaliplatin for Esophagogastric Junction Squamous Cell Carcinoma.",
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"abstract": "Posterior reversible encephalopathy syndrome (PRES) is a neuro-radiologic diagnosis that has become more widely recognized and reported over the past few decades. As such, there are a number of known risk factors that contribute to the development of this syndrome, including volatile blood pressures, renal failure, cytotoxic drugs, autoimmune disorders, pre-eclampsia, and eclampsia. This report documents the first reported case of PRES in a patient with severe alcoholic hepatitis with hepatic encephalopathy and delves into a molecular pathophysiology of the syndrome.",
"affiliations": "Elizabeth S John, Ramy Sedhom, Ishita Dalal, Ranita Sharma, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, United States.;Elizabeth S John, Ramy Sedhom, Ishita Dalal, Ranita Sharma, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, United States.;Elizabeth S John, Ramy Sedhom, Ishita Dalal, Ranita Sharma, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, United States.;Elizabeth S John, Ramy Sedhom, Ishita Dalal, Ranita Sharma, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, United States.",
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"fulltext": "\n==== Front\nWorld J GastroenterolWorld J. GastroenterolWJGWorld Journal of Gastroenterology1007-93272219-2840Baishideng Publishing Group Inc jWJG.v23.i2.pg37310.3748/wjg.v23.i2.373Case ReportPosterior reversible encephalopathy syndrome in alcoholic hepatitis: Hepatic encephalopathy a common theme John Elizabeth S Sedhom Ramy Dalal Ishita Sharma Ranita Elizabeth S John, Ramy Sedhom, Ishita Dalal, Ranita Sharma, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, United StatesAuthor contributions: All authors took care of the patient medically; John ES drafted the report; Sedhom R, Dalal I and Sharma R made critical appraisals of the report.\n\nCorrespondence to: Elizabeth S John, MD, Department of Medicine, Rutgers Robert Wood Johnson Medical School, 1 Robert Wood Johnson Place, MEB 492, New Brunswick, NJ 08901, United States. elizabethjohn17@gmail.com\n\nTelephone: +1-973-5926116\n\n14 1 2017 14 1 2017 23 2 373 376 22 7 2016 6 9 2016 10 10 2016 ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.2017This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.Posterior reversible encephalopathy syndrome (PRES) is a neuro-radiologic diagnosis that has become more widely recognized and reported over the past few decades. As such, there are a number of known risk factors that contribute to the development of this syndrome, including volatile blood pressures, renal failure, cytotoxic drugs, autoimmune disorders, pre-eclampsia, and eclampsia. This report documents the first reported case of PRES in a patient with severe alcoholic hepatitis with hepatic encephalopathy and delves into a molecular pathophysiology of the syndrome.\n\nAlcoholic hepatitisHepatic encephalopathyPosterior reversible encephalopathy syndromeSeizureHeadaches\n==== Body\nCore tip: Posterior reversible encephalopathy syndrome (PRES) has been described in a number of settings, but not in the setting of severe alcoholic hepatitis, as is presented in this case report. There are clear molecular relationships between ammonia, which is detoxified to glutamine in the brain, causing astrocytic swelling, cerebral edema, and vasogenic edema. This vasogenic edema is a pivotal component of PRES and accounts for one of the major hypotheses of the syndrome. Thus, though a clear connection between hyperammonemia and PRES has never been documented, there is a theoretical relationship.\n\nINTRODUCTION\nPosterior reversible encephalopathy syndrome (PRES) is a disorder characterized by various acute neurological symptoms and has been increasingly recognized over the past two decades due to advances in brain imaging. It is identified radiographically by subcortical vasogenic brain edema. PRES has been documented in patients with renal failure, labile blood pressure, cytotoxic drugs, autoimmune disorders, pre-eclampsia and eclampsia[1]. There has been one documented case of PRES in a patient with cirrhosis who presented with gastrointestinal bleeding, hypotension and hepatic encephalopathy[2]. We present the first reported case of PRES in the setting of severe alcoholic hepatitis with hepatic encephalopathy and the absence of the known predisposing factors described to date.\n\nCASE REPORT\nA 40-year-old female was readmitted to the hospital with a seizure following a 3-wk admission for hepatic encephalopathy due to severe alcoholic hepatitis. The patient returned to the hospital in less than 24 h of discharge following a witnessed tonic-clonic seizure at home. She had no prior history of seizures. She did not consume alcohol or non-prescription drugs between discharge and readmission. She reported compliance with prescribed medications at home.\n\nDuring the preceding hospitalization, the patient presented with altered mental status, fever, jaundice, tender hepatomegaly, and a white blood cell count of 14.1 thousand/μL. Altered mental status was gauged by the West Haven Criteria, by which the patient had grade 3 hepatic encephalopathy. Her discriminant function was 99. Hepatic dysfunction was characterized by albumin of 3.0 g/dL, international normalized ratio (INR) of 2.36, ammonia of 300 mcg/dL, and bilirubin of 30.3 mg/dL. Her aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were 241 IU/L and 62 IU/L, respectively. Body mass index was 16.5. Clinical and radiographic features were suggestive of chronic liver disease, including encephalopathy, ascites, asterixis, spider angiomata and esophageal varices without active gastrointestinal bleeding. Liver biopsy and histology were not obtained as the results would not affect management. Her serum ascites albumin gradient was 3.8 gm/dL and confirmed portal hypertension. Despite appropriate therapy with lactulose and rifaximin, the patient remained grade 3 hepatic encephalopathy. Thus, a magnetic resonance imaging (MRI) examination was performed. Although it was a limited study due to patient movement, bilateral temporal parietal restriction was described, raising concern for PRES. There was no evidence of seizure activity on 60-min electroencephalography (EEG) at the time. Despite mild intermittent headaches, she remained stable without focal neurologic deficits, and was discharged home on the recommended steroid taper for alcoholic hepatitis, ciprofloxacin for spontaneous bacterial peritonitis prophylaxis, fluconazole for candidal esophagitis found on upper endoscopy, nadolol for grade 1 esophageal nonbleeding varices, lactulose and rifaximin for hepatic encephalopathy, and spironolactone and furosemide for ascites.\n\nThe patient was readmitted in less than 24 h following a witnessed tonic-clonic seizure. She was intubated for airway protection and rapidly extubated within 24 h. Her admission vital signs included a temperature of 97.2 F, pulse of 95 beats/min, respiratory rate of 8 breaths/min and a blood pressure of 114/78 mmHg. Off sedation, there were no focal neurologic findings. Labs were significant for hemoglobin of 10.0 g/dL, INR of 1.79, prothrombin time of 19.4 s, creatinine of 0.3 mg/dL, bicarbonate of 15.5 mmol/L, anion gap of 21 mEq/L, total bilirubin of 10.8 mg/dL, direct bilirubin of 6.5 mg/dL, alkaline phosphatase of 133 IU/L, ALT of 54 IU/L, and AST of 112 IU/L, all relatively unchanged from her discharge labs. Urine drug screen was negative and alcohol level was undetectable.\n\nA repeat MRI was performed while the patient was post-ictal and grade 3 HE, which showed a high signal intensity in the subcortical, and periventricular white matter of the bilateral temporal and parietal lobes on the fluid attenuated inversion recovery (FLAIR) sequence of MRI was consistent with PRES (Figure 1). The MRI was unchanged from the previous MRI, though it was better quality because there was less artifact from patient movement. EEG showed high focal epileptogenic potential in this same temporal-parietal area. Subsequent neurologic exam revealed right visual field deficits, and psychomotor retardation with subjective complaint of headaches, but no asterixis or other focal deficits. She was started on lacosamide for further seizure prevention and continued on lactulose and rifaximin. Fluconazole was switched to itraconazole to prevent the lowering of her seizure threshold. Prior to discharge, her neurologic deficits and headaches had completely resolved.\n\nFigure 1 Flair hyperintense signal axial view involving the cortex and subcortical white matter involving the parietal and temporal lobes, consistent with posterior reversible encephalopathy syndrome.\n\nDISCUSSION\nPRES, first described in 1996 in the New England Journal of Medicine, is a clinic neuro-radiological diagnosis. While the pathogenesis of PRES is not fully understood, two prevailing hypotheses have been proposed, but neither has been fully validated thus far. The more popular theory purports that severe and rapidly developing hypertension can devastate auto-regulation, resulting in hyperperfusion with endothelial injury/vasogenic edema[3]. The posterior brain is more affected by hyperperfusion, as minimal sympathetic innervation exists in the posterior fossa. The original hypothesis conversely suggests that hypoperfusion causes vasoconstriction, resulting in brain ischemia and consequent vasogenic edema[4].\n\nThe increased intrahepatic resistance from cirrhosis causes portal hypertension, and is worsened by hepatic and non-hepatic endothelial dysfunction[4], a component found in the prevalent theory of PRES pathophysiology. Specifically, hypoactive endothelial cells decrease nitric oxide production that consequently initiates portal hypertension. This, in turn, results in endothelial dysfunction in the splanchnic and systemic circulation (extrahepatic). There is a subsequent superfluous amount of vasodilators, resulting in vasodilation that further contributes to exacerbating the portal hypertension[4].\n\nThe pathophysiology of hepatic encephalopathy is not completely understood, but ammonia has been recognized as a pivotal player in the process. There are two forms of ammonia - ammonium (NH4+) and ammonia (NH3) - the latter of which is more predominant in alkalotic states and described in approximately 70% of patients with decompensated liver disease[5]. As the brain has no inherent cycle of urea metabolism, ammonia reaching the astrocytes is detoxified by glutamine synthetase in the presence of glutamate to form glutamine. Glutamate is a major transmitter involved in neuro-excitation in 80% of synapses. Glutamine over-production promotes swelling of astrocytes, which results in cerebral edema, resulting in intracranial pressure[6]. In fact, using magnetic resonance diffusion tensor imaging, an increase in interstitial brain water in patients with cirrhosis and hepatic encephalopathy has been shown. In this study, the higher grades of hepatic encephalopathy corresponded to an increased brain water content. Similarly, treating hyperammonemia resulted in decreased brain water content[7]. Lastly, hyperammonemia has been implicated in the dysregulation of cerebral blood flow and consequent cerebral vasodilation causing vasogenic edema[8,9]. It is the presence of additional vasogenic edema that has also been implicated in the specific pathogenesis of PRES. As evidenced, portal hypertension and hepatic encephalopathy result in changes that are concurrent with the changes found in PRES. However, there is a dearth of literature regarding PRES and hepatic encephalopathy in the setting of portal hypertension irrespective of the underlying etiology.\n\nClinical manifestations of PRES have been variable. Most frequently it presents as various degrees of encephalopathy or seizures. It can also manifest as headaches, visual disturbances, other focal neurological deficits, or status epileptics[10]. Symptoms are usually acute or subacute. As stated earlier, symptoms are most often seen in the setting of renal failure, labile blood pressures, autoimmune disorders, preeclampsia/eclampsia or cytotoxic or immunosuppressive drugs such as calcineurin inhibitors, cyclosporine, and cisplatin, but not steroids[10]. The patient was on steroids, but there has been no defined relationship in the literature between the use of steroids and PRES. There have been sparse case reports of PRES occurring in patients with acute hepatic failure[11], and one in a cirrhotic patient[1] with hepatic encephalopathy. Our patient was hemodynamically stable and did not present with any of these known risk factors. Her ammonia level was significantly elevated despite lactulose and rifaximin therapy. The hyperammonemia could have been the triggering factor for developing PRES, while the fluconazole used to treat esophageal candidiasis likely lowered her seizure threshold, resulting in the witnessed tonic-clonic seizure.\n\nRadiologic confirmation is an important component of diagnosis. Neuroradiologic images of PRES show characteristic white-gray matter edema predominantly involving the posterior region of the brain and best seen with brain MRI. Our patient had bilateral temporal and parietal lobe findings, as seen in Figure 1, which are two common areas that are affected in PRES. It can also frequently be seen in the parieto-occipital region, watershed regions, and frontal lobes.\n\nTreatment of PRES has not been well studied; symptoms usually resolve once the underlying cause has been treated. Patients with seizures, such as our patient, should be placed on anti-epileptic medications. Once the underlying disorder has been treated, prognosis is usually favorable. Our case poses an interesting challenge because it introduces another potential etiology of PRES, which has not been studied in the past. Further research is needed to better understand the pathophysiology of PRES, a neurologic entity that can occur in many clinical conditions. Other possible etiologies, including exaggerated immune response or cytokine release may enhance systemic endothelial activation. This case adds to the literature of potential etiologies leading to PRES, an extremely rare clinical and radiologic diagnosis.\n\nIn conclusion, this is the first reported case of acute alcoholic hepatitis with hepatic encephalopathy developing PRES in the absence of known risk factors such as hypotension, ischemia, and blood pressure fluctuations.\n\nCOMMENTS\nCase characteristics\nThe patient is a known alcoholic, who had presented with altered mental status.\n\nClinical diagnosis\nOn physical exam, the patient had tender hepatomegaly, jaundice, asterixis, and altered mental status consistent with grade 3 hepatic encephalopathy; on her readmission, she presented with a post-ictal state after having a witnessed seizure.\n\nDifferential diagnosis\nThe seizures were attributed to posterior reversible encephalopathy syndrome (PRES), but other things considered included alcohol withdrawal, hepatic encephalopathy, and drug abuse.\n\nLaboratory diagnosis\nThe patient was initially admitted with fever, jaundice, tender hepatomegaly, leukocytosis, hyperammonemia, and a history of heavy alcohol abuse. Upon her re-admission when she presented with seizures; she was re-admitted with similar labs.\n\nImaging diagnosis\nThe imaging was the crux of the case, as magnetic resonance imaging revealed PRES, though the patient did not have any of the typical risk factors for developing PRES.\n\nPathological diagnosis\nThere were no pathological diagnoses made in this case.\n\nTreatment\nThe patient was treated with lactulose and rifaximin on her first admission; during the re-admission, she was treated with lacosamide, and continued with the treatment of hepatic encephalopathy, including lactulose and rifaximin.\n\nRelated reports\nThere is one other case of PRES in a patient with cirrhosis who presented with gastrointestinal bleeding, hypotension and hepatic encephalopathy, however the case presented in this report is unique in that there is no associated volatile blood pressure, which is well documented as a cause of PRES.\n\nTerm explanation\nPRES: Posterior reversible encephalopathy syndrome is a radiographic condition that has been well documented in patients with renal failure, labile blood pressure, cytotoxic drugs, autoimmune disorders, pre-eclampsia and eclampsia.\n\nExperiences and lessons\nIt is crucial to recognize the relationship between hyperammonemia and hepatic encephalopathy and PRES as a side effect as avoiding medications that can further lower the seizure threshold.\n\nPeer-review\nThe strengths of this article include the novel proposed pathophysiologic relationship between hyperammonemia and PRES, an association that has not been explored in the past. The weakness of this article is that there was no liver biopsy to prove hepatic impairment, though this can be clinically determined.\n\nManuscript source: Unsolicited manuscript\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry of origin: United States\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nInformed consent statement: Informed consent was acquired from the patient.\n\nConflict-of-interest statement: None of the authors have any financial disclosures or conflicts of interest.\n\nPeer-review started: July 25, 2016\n\nFirst decision: August 22, 2016\n\nArticle in press: October 10, 2016\n\nP- Reviewer: McMillin MA, Yadav SK S- Editor: Yu J L- Editor: Filipodia E- Editor: Liu WX\n==== Refs\n1 Fugate JE Rabinstein AA Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions Lancet Neurol 2015 14 914 925 26184985 \n2 Chawla R Smith D Marik PE Near fatal posterior reversible encephalopathy syndrome complicating chronic liver failure and treated by induced hypothermia and dialysis: a case report J Med Case Rep 2009 3 6623 19830117 \n3 Bartynski WS Boardman JF Catheter angiography, MR angiography, and MR perfusion in posterior reversible encephalopathy syndrome AJNR Am J Neuroradiol 2008 29 447 455 18079186 \n4 Iwakiri Y Groszmann RJ Vascular endothelial dysfunction in cirrhosis J Hepatol 2007 46 927 934 17391799 \n5 Butterworth RF Pathogenesis of hepatic encephalopathy in cirrhosis: the concept of synergism revisited Metab Brain Dis 2015 Nov 2; Epub ahead of print \n6 Lemberg A Fernández MA Hepatic encephalopathy, ammonia, glutamate, glutamine and oxidative stress Ann Hepatol 2009 8 95 102 19502650 \n7 Kale RA Gupta RK Saraswat VA Hasan KM Trivedi R Mishra AM Ranjan P Pandey CM Narayana PA Demonstration of interstitial cerebral edema with diffusion tensor MR imaging in type C hepatic encephalopathy Hepatology 2006 43 698 706 16557540 \n8 Larsen FS Adel Hansen B Pott F Ejlersen E Secher NH Paulson OB Knudsen GM Dissociated cerebral vasoparalysis in acute liver failure. A hypothesis of gradual cerebral hyperaemia J Hepatol 1996 25 145 151 8878774 \n9 Blei AT Larsen FS Pathophysiology of cerebral edema in fulminant hepatic failure J Hepatol 1999 31 771 776 10551405 \n10 Servillo G Bifulco F De Robertis E Piazza O Striano P Tortora F Striano S Tufano R Posterior reversible encephalopathy syndrome in intensive care medicine Intensive Care Med 2007 33 230 236 17119920 \n11 Mettananda S Fernando AD Ginige N Posterior reversible encephalopathy syndrome in a survivor of valproate-induced acute liver failure: a case report J Med Case Rep 2013 7 144 23724918\n\n",
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"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Successful Drug Management with Dabigatran and Idarucizumab to Address Embolic and Hemorrhagic Complications for Asymptomatic and Traumatic Subdural Hematoma with Non-valvular Atrial Fibrillation.",
"title_normalized": "a case of successful drug management with dabigatran and idarucizumab to address embolic and hemorrhagic complications for asymptomatic and traumatic subdural hematoma with non valvular atrial fibrillation"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-059314",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "BACKGROUND\nThe maximum axial diameter (MAD) of a fusiform abdominal aortic aneurysm (AAA) is an indicator of the risk of expansion or rupture. Apart from smoking and MAD itself, few expansion risk factors have been reported. In this study, we investigated expansion risk factors for AAA.Methods and Results:This retrospective cohort study included 176 patients who attended Tohoku University Hospital with infrarenal fusiform AAA. AAA expansion rate was determined on multidetector computed tomography, and the correlations between expansion rate and the clinical data were analyzed. The median expansion rate was 2.405 mm/year. On univariate analysis, a significant positive correlation with expansion rate was observed for the initial MAD (P<0.001) and significant negative correlations for oral angiotensin receptor blocker usage (P=0.025), height (P=0.005), body weight (P=0.017), total cholesterol (P=0.007), low-density lipoprotein cholesterol (P=0.004), and HbA1c (P=0.037). On logistic regression analysis, significant positive associations with expansion rate were observed for initial MAD (P<0.001) and oral steroid usage (P=0.029) and a negative association for height (P=0.041).\n\n\nCONCLUSIONS\nOral steroid usage is an important risk factor for AAA expansion, independent of other risk factors of atherosclerosis and MAD.",
"affiliations": "Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital.;Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital.;Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital.;Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital.;Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital.;Department of Vascular Surgery, Japanese Red Cross Ishinomaki Hospital.;Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital.;Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital.;Department of Vascular Surgery, Japan Community Health Care Organization Sendai Hospital.;Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital.;Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital.;Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital.",
"authors": "Tajima|Yuta|Y|;Goto|Hitoshi|H|;Ohara|Masato|M|;Hashimoto|Munetaka|M|;Akamatsu|Daijiro|D|;Shimizu|Takuya|T|;Miyama|Noriyuki|N|;Tsuchida|Ken|K|;Kawamura|Keiichiro|K|;Umetsu|Michihisa|M|;Suzuki|Shunya|S|;Ohuchi|Noriaki|N|",
"chemical_list": "D013256:Steroids",
"country": "Japan",
"delete": false,
"doi": "10.1253/circj.CJ-16-0902",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1346-9843",
"issue": "81(12)",
"journal": "Circulation journal : official journal of the Japanese Circulation Society",
"keywords": "Abdominal aortic aneurysm; Abdominal aortic aneurysm expansion rate; Atherosclerosis; Maximum axial diameter; Oral steroid",
"medline_ta": "Circ J",
"mesh_terms": "D000368:Aged; D017544:Aortic Aneurysm, Abdominal; D001019:Aortic Rupture; D001827:Body Height; D018450:Disease Progression; D006801:Humans; D061330:Multidetector Computed Tomography; D012189:Retrospective Studies; D012307:Risk Factors; D013256:Steroids",
"nlm_unique_id": "101137683",
"other_id": null,
"pages": "1774-1782",
"pmc": null,
"pmid": "28674268",
"pubdate": "2017-11-24",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Oral Steroid Use and Abdominal Aortic Aneurysm Expansion - Positive Association.",
"title_normalized": "oral steroid use and abdominal aortic aneurysm expansion positive association"
} | [
{
"companynumb": "JP-PFIZER INC-2017544824",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Natalizumab (NTZ) is a monoclonal antibody with an immunosuppressive effect that reduces the inflammation of the central nervous system, and it has been used for the treatment of relapsing-remitting multiple sclerosis (RRMS). In patients with low cellular immune response, systemic mycosis arising from endemic areas may occur.\n\n\n\nIn this article, we will describe a case of paracoccidioidomycosis as a complication to treatment with NTZ in an RRMS patient.",
"affiliations": "Department of Neurology, Central Institute, Clínicas Hospital, University of São Paulo, São Paulo, Brazil.;Facid Devry Faculty of Medicine, Teresina, Brazil.;Department of Neurology, Federal University of Piauí, Teresina, Brazil.;Department of Neurology, Federal University of Piauí, Teresina, Brazil.;Division of Neurosurgery, Department of Neurology, University of São Paulo, São Paulo, Brazil.",
"authors": "Almeida|Kelson James|KJ|0000-0002-6299-7323;Barreto-Soares|Raissa Viera|RV|;Campos-Sousa|Raimundo Nonato|RN|;Campos-Sousa|Maria Graças|MG|;Bor-Seng-Shu|Edson|E|",
"chemical_list": "D007155:Immunologic Factors; D000069442:Natalizumab",
"country": "England",
"delete": false,
"doi": "10.1177/1352458518763091",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "24(7)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "Multiple sclerosis; mycosis; natalizumab; paracoccidioidomycosis",
"medline_ta": "Mult Scler",
"mesh_terms": "D006801:Humans; D016867:Immunocompromised Host; D007155:Immunologic Factors; D008172:Lung Diseases, Fungal; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D000069442:Natalizumab; D010229:Paracoccidioidomycosis",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "1002-1004",
"pmc": null,
"pmid": "29649930",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pulmonary paracoccidioidomycosis associated with the use of natalizumab in multiple sclerosis.",
"title_normalized": "pulmonary paracoccidioidomycosis associated with the use of natalizumab in multiple sclerosis"
} | [
{
"companynumb": "BR-BIOGEN-2018BI00560904",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NATALIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "All-trans-retinoic acid represents a major progress that has made acute promyelocytic leukemia the most curable subtype of acute myeloid leukemia in adults. Although all-trans-retinoic acid is usually well tolerated, some patients develop the retinoic acid syndrome, characterized by unexplained fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, pleural and pericardial effusions, episodic hypotension, and acute renal failure. Further studies of growth factor expression and modulation of adhesion molecules are warranted to provide further insights into the pathogenesis of the syndrome and may lead to its prevention.",
"affiliations": "1Department of Medicine; and 2Department of Hematology-Oncology, University of Toledo, Toledo, OH.",
"authors": "Tariq|Zeeshan|Z|;Phinney|Richard C|RC|;Mohamed|Iman|I|",
"chemical_list": "D000970:Antineoplastic Agents; D014212:Tretinoin",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0b013e31822aeece",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "21(2)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000970:Antineoplastic Agents; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008875:Middle Aged; D013577:Syndrome; D014212:Tretinoin",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e28-30",
"pmc": null,
"pmid": "23567795",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A case of life-threatening retinoic acid syndrome and review of literature.",
"title_normalized": "a case of life threatening retinoic acid syndrome and review of literature"
} | [
{
"companynumb": "US-WATSON-2014-27068",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TRETINOIN"
},
"drugadditional": null,
"d... |
{
"abstract": "Paracoccidioidomycosis is a systemic disease endemic to subtropical areas in Central and South America caused by a dimorphic fungus known as Paracoccidioides brasiliensis. Central nervous system involvement is a severe complication of the systemic disease, and has been found in approximately 13% of patients. This paper describes the case of a patient whose computed tomography scan and magnetic resonance imaging showed a single tumor-like lesion in the brainstem. Histopathological and mycological examinations of stereotactic biopsy smears showed the characteristic yeast cells that confirmed the diagnosis of neuroparacoccidioidomycosis.",
"affiliations": "Division of HIV/AIDS, \"F. J. Muñiz\" Infectious Diseases Hospital; Buenos Aires, Argentina - marcelocorti@fibertel.com.ar.",
"authors": "Corti|M|M|;Trione|N|N|;Risso|D|D|;Soto|I|I|;Villafañe|M F|MF|;Yampolsky|C|C|;Negroni|R|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/197140091002300416",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1971-4009",
"issue": "23(4)",
"journal": "The neuroradiology journal",
"keywords": null,
"medline_ta": "Neuroradiol J",
"mesh_terms": null,
"nlm_unique_id": "101295103",
"other_id": null,
"pages": "454-8",
"pmc": null,
"pmid": "24148639",
"pubdate": "2010-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Disseminated paracoccidioidomycosis with a single brainstem lesion. A case report and literature review.",
"title_normalized": "disseminated paracoccidioidomycosis with a single brainstem lesion a case report and literature review"
} | [
{
"companynumb": "AR-LUPIN PHARMACEUTICALS INC.-2022-06086",
"fulfillexpeditecriteria": "2",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
... |
{
"abstract": "Two corticosteroid-treated patients with cutaneous cryptococcal infection are described. One patient had pustulous lesions on the back of his left hand and cellulitis of his left forearm, the other patient had ulcerous lesions of the right forearm and cellulitis of the right lower leg. In both cases diagnosis was suggested by histopathological examination of a biopsy and confirmed by culture. One patient may have had disseminated cryptococcal disease as suggested by a positive cryptococcal capsular antigen test, the other had no evidence of dissemination. Treatment consisted of oral fluconazole for six weeks. One patient died of an unrelated cause after four weeks treatment. Secondary antifungal prophylaxis was not given. Cutaneous cryptococcal infections are described in AIDS patients, but only seldom observed in other immunocompromised patients. Early recognition of the cutaneous lesions is important, as they can be the first sign of disseminated cryptococcosis. Untreated, the mortality of this disease is high. Therapy consists of amphotericin B with or without flucytosine. Fluconazole may be valuable alternative. The optimal treatment regimen and duration are not defined yet. Contrary to AIDS patients with cryptococcal infection, who need life-long secondary antifungal prophylaxis in order to prevent relapses, suppressive treatment is not indicated for immunocompromised non-AIDS patients.",
"affiliations": "Department of Internal Medicine, University Hospitals, Leuven, Belgium.",
"authors": "Vandersmissen|G|G|;Meuleman|L|L|;Tits|G|G|;Verhaeghe|A|A|;Peetermans|W E|WE|",
"chemical_list": "D000935:Antifungal Agents; D015725:Fluconazole",
"country": "England",
"delete": false,
"doi": "10.1080/17843286.1996.11718496",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "51(2)",
"journal": "Acta clinica Belgica",
"keywords": null,
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D002481:Cellulitis; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D003881:Dermatomycoses; D015725:Fluconazole; D006801:Humans; D008297:Male; D012883:Skin Ulcer",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "111-7",
"pmc": null,
"pmid": "8693868",
"pubdate": "1996",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cutaneous cryptococcosis in corticosteroid-treated patients without AIDS.",
"title_normalized": "cutaneous cryptococcosis in corticosteroid treated patients without aids"
} | [
{
"companynumb": "BE-PFIZER INC-2020470265",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "To present the pharmacological evaluation process in a case of a polymedicated patient presenting with toxic epidermal necrolysis (TEN).\nA 75-year-old Caucasian polymedicated woman had been treated for hip pain with nonsteroidal anti-inflammatory drugs and pregabalin in the months preceding the apparition of an expanding papulo-erythematous rash. She had also started using new medicated eye drops for glaucoma. She presented to the emergency department of a regional hospital where all of her medications were stopped. The patient was transferred and admitted to a tertiary-care teaching hospital's specialized burn unit for significant cutaneous detachment. It was estimated that 70% to 80% of the body surface area was affected. Skin biopsy showed keratinocyte necrosis with a partial detachment of the epidermis leading to a diagnosis of TEN. The reaction ceased to progress 2 days after the discontinuation of her medications. A complete reepithelialization was objectified after 10 days. A series of steps were followed by the hospital pharmacist to determine which drugs were the most probable culprits. A complete pharmacological history was obtained and a timeline for medication use in the 3 months preceding rash apparition was established. A review of the literature was done to determine the drugs' relationships to Steven-Johnson syndrome or TEN. Using the algorithm of drug causality for epidermal necrolysis (ALDEN) score, it was determined that naproxen, pregabalin, and brinzolamide-timolol drops were all possible culprits.\nA systematic method for pharmacological evaluation of a polymedicated patient with TEN is presented. Naproxen, pregabalin, and brinzolamide-timolol drops were all retained as possible culprits.",
"affiliations": "Department of Pharmacy, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.;Department of Pharmacy, Centre Intégré de Santé et de Services Sociaux de la Montérégie-Est, Longueuil, Québec, Canada.;Department of Pharmacy, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.;Department of Pharmacy, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.;Department of Pharmacy, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.",
"authors": "Khazaka|Michael|M|https://orcid.org/0000-0002-0004-0964;Laverdière|Jeanne|J|;Bouchard|Audrey|A|;Ferreira|Victor|V|;Mathieu|Alexandre|A|https://orcid.org/0000-0002-4224-8552",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190020934295",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "34(6)",
"journal": "Journal of pharmacy practice",
"keywords": "adverse reaction; brinzolamide–timolol; naproxen; pregabalin; toxic epidermal necrolysis",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004636:Emergency Service, Hospital; D005260:Female; D006760:Hospitalization; D006801:Humans; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "970-974",
"pmc": null,
"pmid": "32588724",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Identification of Possible Causative Agents in a Polymedicated Patient Presenting With Toxic Epidermal Necrolysis.",
"title_normalized": "identification of possible causative agents in a polymedicated patient presenting with toxic epidermal necrolysis"
} | [
{
"companynumb": "CA-AUROBINDO-AUR-APL-2020-032129",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional": "1"... |
{
"abstract": "Intestinal opportunistic infections are often caused by unicellular parasites. Individuals with decreased immunity are particularly susceptible to infection by said microorganisms, and when they are infected, diarrhea can be the main clinical manifestation. However, intestinal parasites have rarely been taken into account in intestinal disorders. In our study, an investigation was conducted to determine the prevalence of intestinal micro-pathogens, such as Cryptosporidium, Giardia, Blastocystis, and microsporidia, in hospitalized patients with different immunological statuses. The study at hand indicates that protozoan parasitic infections are rare among immunodeficient patients in Poland. The overall prevalence of micro-pathogens among participants was 4.6%; it was three times higher in adults (12.5%) than in children (2.3%). Cryptosporidium and Cyclospora species (Apicomplexa) were diagnosed as the main cause of heavy diarrhea. Accordingly, adult patients were positive mainly for Blastocystis and microsporidia, while children were more often infected with the Cryptosporidium species.",
"affiliations": "Department of Parasitology, Faculty of Biology, University of Warsaw, Warsaw, Poland. mabed@biol.uw.edu.pl.;Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland.;Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland.;Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland.;Department of Parasitology, Faculty of Biology, University of Warsaw, Warsaw, Poland.;Immunology Clinic, Children's Memorial Health Institute, Warsaw, Poland.;Department of Pediatry, Children's Hospital, Otwock, Poland.;Department of Parasitology, Faculty of Biology, University of Warsaw, Warsaw, Poland.",
"authors": "Bednarska|Małgorzata|M|;Jankowska|Irena|I|;Pawelas|Andrzej|A|;Piwczyńska|Karolina|K|;Bajer|Anna|A|;Wolska-Kuśnierz|Beata|B|;Wielopolska|Małgorzata|M|;Welc-Falęciak|Renata|R|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00436-018-5976-6",
"fulltext": "\n==== Front\nParasitol ResParasitol. ResParasitology Research0932-01131432-1955Springer Berlin Heidelberg Berlin/Heidelberg 597610.1007/s00436-018-5976-6Original PaperPrevalence of Cryptosporidium, Blastocystis, and other opportunistic infections in patients with primary and acquired immunodeficiency Bednarska Małgorzata mabed@biol.uw.edu.pl 1Jankowska Irena 2Pawelas Andrzej 3Piwczyńska Karolina 2Bajer Anna 1Wolska-Kuśnierz Beata 4Wielopolska Małgorzata 5Welc-Falęciak Renata 11 0000 0004 1937 1290grid.12847.38Department of Parasitology, Faculty of Biology, University of Warsaw, Warsaw, Poland 2 0000 0001 2232 2498grid.413923.eDepartment of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, Children’s Memorial Health Institute, Warsaw, Poland 3 0000 0001 2205 7719grid.414852.eDepartment of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland 4 0000 0001 2232 2498grid.413923.eImmunology Clinic, Children’s Memorial Health Institute, Warsaw, Poland 5 Department of Pediatry, Children’s Hospital, Otwock, Poland Section Editor: Kevin S.W. Tan\n\n26 6 2018 26 6 2018 2018 117 9 2869 2879 6 2 2018 15 6 2018 © The Author(s) 2018Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Intestinal opportunistic infections are often caused by unicellular parasites. Individuals with decreased immunity are particularly susceptible to infection by said microorganisms, and when they are infected, diarrhea can be the main clinical manifestation. However, intestinal parasites have rarely been taken into account in intestinal disorders. In our study, an investigation was conducted to determine the prevalence of intestinal micro-pathogens, such as Cryptosporidium, Giardia, Blastocystis, and microsporidia, in hospitalized patients with different immunological statuses. The study at hand indicates that protozoan parasitic infections are rare among immunodeficient patients in Poland. The overall prevalence of micro-pathogens among participants was 4.6%; it was three times higher in adults (12.5%) than in children (2.3%). Cryptosporidium and Cyclospora species (Apicomplexa) were diagnosed as the main cause of heavy diarrhea. Accordingly, adult patients were positive mainly for Blastocystis and microsporidia, while children were more often infected with the Cryptosporidium species.\n\nKeywords\nCryptosporidium spp.C. felisBlastocystis hominisOpportunistic parasitesPID patientsDiarrheaMinistry of Science and Higher Education in Warsaw, PolandN N404101036Bednarska Małgorzata issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2018\n==== Body\nIntroduction\nIntestinal opportunistic infections are caused by viruses, bacteria, or unicellular parasites. Patients with impaired immunity are particularly susceptible to infections which may develop into severe illness. The first symptoms of intestinal parasitic infections are diarrhea and other intestinal disorders, such as cramping abdominal pains, nausea, vomiting, or low-grade fever. Diarrhea is ordinarily chronic and prolonged in the course of opportunistic diseases (Pierce and Kirkpatrick 2009; Nimri and Meqdam 2004). It can lead to dehydration (Bednarska et al. 2015), weight loss (Kucik et al. 2004), or even death (Cheng et al. 2005). Cryptosporidium parvum and Cryptosporidium hominis are prevailing microparasites in patients with immunodeficiency (Khan et al. 2017; Fayer 2010; Bajer et al. 2008). As of today, approximately 30 species and genotypic variants of Cryptosporidium have been described in mammals (Siński et al. 1998; Bajer et al. 2011), birds (Helmy et al. 2017), reptiles (Paiva et al. 2013), amphibian (Jirků et al. 2008), and fish (Ryan 2010). Most human diseases are provoked by C. hominis and C. parvum species which can infect more than 100 species of mammals (Caccio et al. 2005). Some less common species typical for animals, such as Cryptosporidium meleagridis, Cryptosporidium felis, Cryptosporidium canis, Cryptosporidium muris, and Cryptosporidium suis, have been reported mainly in humans with immunodeficiency (Cacciò et al. 2002; Wolska-Kusnierz et al. 2007; Bajer et al. 2008; Xiao 2010). It should be highlighted that C. meleagridis, previously described only in Turkey, has been noted in 1% of cryptosporidiosis in the UK (Mosier and Oberst 2000) and 10–20% in Peru (Cama et al. 2008).\n\nOther opportunistic parasite species, such as microsporidia, Cyclospora, Cystoisospora, and Blastocystis, may also be associated with gastrointestinal diseases. It is currently unclear whether Blastocystis is a pathogen, a commensal, or an opportunistic organism. In favorable conditions, it causes intestinal disorders, but the infection may be either self-limiting or asymptomatic (Tan 2004; Scanlan and Stensvold 2013).\n\nCyclospora and Cystoisospora are most commonly associated with diarrhea in travelers, especially those visiting endemic areas (Legua and Seas 2013). Parasitic infections may cause a significant problem in immunocompromised persons (very young, elderly, after transplantation, and with AIDS) (Forrest 2004; Lewthwaite et al. 2005; Barsoum 2004). Transplant recipients are more likely to suffer from parasitic invasions as a consequence of immunosuppressive therapy. In general, gastrointestinal infections have been increasingly reported in this risk group. There are a few epidemiological studies carried out worldwide to examine the intestinal parasitic infections in liver or renal transplant recipients (Azami et al. 2010; Batista et al. 2011; Bednarska et al. 2013, 2014; Krause et al. 2012).\n\nMicrosporidia are a group of pathogens still poorly recognized and diagnosed in a human population. Of the 15 microsporidia species identified as human pathogens, two species cause gastrointestinal disease: Enterocytozoon bieneusi and Encephalitozoon intestinalis—the former being more commonly identified in solid-organ transplant recipients (Anane and Attouchi 2010).\n\nIn our study, the prevalence of intestinal micro-pathogens in hospitalized patients with different immunological statuses is defined. Furthermore, the pathogenicity detected in the patients with Cryptosporidium spp. and Blastocystis hominis is discussed.\n\nMaterials and methods\nStool samples\nThe study was carried out in three specialized hospitals in Warsaw along with its surrounding area during 2007–2015. Fecal samples were collected in hospital wards by medical practitioners for the purposes of routine bacteriological examinations and, subsequently, subjected to further retrospective examinations. Written informed consent was obtained from all patients, and the study protocol followed ethical guidelines of the 2013 Declaration of Helsinki. All ethical approvals for the study have been obtained according to Polish regulations. Fresh stool samples were obtained on two, three, or more occasions from patients and stored at + 4 °C. Samples were obtained from 285 patients (121 male and 164 female) with different immune statuses in the following departments: Children’s Memorial Health Institute in Warsaw (CMHI): (1) Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics Clinic (CZW) (n = 147; 58M/89F); (2) the Immunology Clinic (CZD) (n = 34; 20M/14F); (3) Pediatric Department in General Hospital in Otwock (OT) (n = 40; 13M/27F); (4) Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education (ON) (n = 64; 30M/34F). The patients were subdivided into two groups according to their age (221 under and 64 above 18 years old) and three groups based on their immunological status (Table 1).Table 1 Characteristic of immunodeficiency degree use in this study. Number and distribution of the patients due to their immunological status\n\nDegree of immunodeficiency (DOI)\tImmunological status\tImmune resistance decreasing factor\tNumber of patients\t\n0\tImmunocompetent\tNo\t47\t\n1\tMild immunodeficient\tCVID, primary IgA immunodeficiency, chronic disease or transplant and 1–2 immunosuppressant drugs (low dose)\t155\t\n2\tHeavy immunodeficient\tPID, high doses of post-transplant or another medical immunosuppressant (2–3 drugs)\t83\t\n\n\nThe first group involved 147 patients after liver transplantation under pharmacological immunosuppression [tacrolimus (TAC), sirolimus (SIR), cyclosporine (CSR) alone or collectively with steroids (ST), mycophenolate mofetil (MMF), or azathioprinum (AZP)]. The patients rarely manifested diarrhea or other intestinal disorders (6/147). The second group of children consisted of 34 patients, often with diarrhea (22/34), who presented impaired immunity due to confirmed (n = 32) or suspected (n = 2) primary immunodeficiencies (PID). The third group comprised 40 immunocompetent children with prolonged intestinal disorder (19/40) of unknown etiology. The fourth group consisted of 64 adult patients who presented acquired immunity disorders resulting from various acute diseases [Crohn’s disease (CD), colitis ulcerosa (UC), Clostridium difficile infection (CDI), Cytomegalovirus infections (CMV), rheumatoid arthritis (RAS), autoimmune enteropathy (AIE), hypereosinophilic syndrome (HES), common variable immunodeficiency (CVID), cholangiocarcinoma (CCC), unspecified immune resistance (UIR), radiotherapy (RTx)] and/or used drugs [glucocorticoids (GKS), AZP, 6-mercaptopurine (6-MP), MMF, Infliximabum (IFX)]. Most patients from this group presented prolonged diarrhea and/or other intestinal symptoms (54/64) often up to several months.\n\nStaining of fecal smears\nFecal smears were made from fresh stool specimens, which were air-dried, fixed in methanol, and stained with Ziehl-Neelsen (AquaMed, Poland) for Cryptosporidium spp. This method is highly effective in Cyclospora cayetanensis detection. The modified Weber’s chromotrope-based staining, i.e. trichrome staining (Chromotrope 2R Para-Pak Trichrome Stain, Meridian Diagnostics, Cincinnati, OH, USA) (Weber et al. 1992), was used for the E. bieneusi and Encephalitozoon spp. diagnoses. Smears were examined under oil immersion (× 1000 magnification). Indirect immunofluorescence assay (IFA) was performed for the verification or detection of Cryptosporidium and/or Giardia infections (Merifluor Cryptosporidium/Giardia kit, Meridian Diagnostics, USA) and diagnosed by direct immunofluorescence microscopy (× 400 magnification).\n\nPCR analysis\nFor DNA extraction, stool specimens were first concentrated by sedimentation (Bednarska et al. 2007). DNA extraction and purification were carried out using QIAamp DNA Stool Mini Kit (Qiagen), following the manufacturer’s protocol. Different sets of primers were used for PCR amplification with respect to the parasite species. A nested-PCR protocol was used to amplify the 18S rRNA gene fragments of Cryptosporidium spp. using primers previously described by Xiao et al. (1999). Additionally, a set of primers for Apicomplexa was used to confirm infection with C. felis (Herwaldt et al. 2003).\n\nThe next, “general” primers described by Raynaud et al. (1998) were used to amplify a 1200 bp conserved region of small-subunit ribosomal RNA genes (SSU-rDNA) with the aim of searching the range of human infecting microsporidial species, including Encephalitozoon cuniculi, Encephalitozoon hellem, E. intestinalis, and E. bieneusi. Species-specific primers were used to amplify a region of 545 bp from the SSU-rDNA of E. intestinalis (Valencáková et al. 2005), and species-specific primers were used to amplify a 607 bp fragment of the SSU-rDNA of E. bieneusi (da Silva et al. 1996).\n\nBlastocystis hominis DNA was detected by PCR, previously described by Alfellani et al. (2013), to amplify the region of 600 bp from the SSU-rDNA.\n\nInfection with C. cayetanensis was detected by microscopic methods and confirmed through nested PCR protocols used to amplify the 18S rRNA gene fragments using the published primer sets and thermal profiles. The nested PCR was performed to amplify a 500-bp fragment of C. cayetanensis 18S rDNA (Sulaiman et al. 2014).\n\nAll PCR products were subjected to electrophoresis in a 1.5% agarose gel stained with Midori Green stain (Nippon Genetics GmbH) and sequenced by a private company (Genomed S.A., Poland).\n\nStatistical analysis\nSPSS 21 software was used for analysis. Patients presenting with diarrhea were compared with those without such symptoms. By the same token, adults and minors were compared.\n\nBoth the correlation between the degree of suppression and the occurrence of invasion, as well as the occurrence of diarrhea and the number of parasitic infections, were analyzed.\n\nResults\nOut of the 283 patients (46 immunocompetent and 237 immunocompromised), a total of 5% (n = 14) were infected with intestinal parasites detected by microscopic, immunofluorescent, and/or PCR techniques. Additionally, three transplant recipients who were minors tested positive for E. coli bacteria strains which were closely related to enteroinvasive strains (99% homology) (Table 2).Table 2 Microbiological and clinical features of patients with microparasitic infection\n\nNo.\tPIC\tSex/age\tStatus immuno/(DI)\tTransplant/another illness\tSymptoms\tParasite species\tDiagnosticmethods/ref.\t\n1\t9/04/CZD\tM/4\tPID, Hiper IgM (2)\tBone marrow\tProlonged diarrhea\t\nC. meleagridis\n\tZ-N, IFA, PCR (Wolska-Kusnierz et al. 2007)\t\n2\t17/05/CZD\tM/5\tPID, Sclerosis cholangitis, CD40 ligand deficiency (2)\tBone marrow\tProlonged diarrhea\tCryptosporidium sp.\tZ-N, IFA, PCR (Wolska-Kusnierz et al. 2007)\t\n3\t35/07/CZD\tF/2\tND (ND)\tNo\tDiarrhea\t\nG. intestinalis\n\tIFA\t\n4\t204/CZW\tM/3\tPhI/.TAC, MMF (2)\tLiver\tNo\t\nE. coli\n\tPCR\t\n5\t213/CZW\tF/7\tPhI/.TAC, MMF (1)\tLiver\tNo\t\nE. coli\n\tPCR\t\n6\t220/CZW\tF/6\tPhI/TAC, MMF (1)\tLiver\tDiarrhea\t\nE. coli\n\tPCR\t\n7\t259/CZW\tF/16\tPhI/TAC, MMF (2)\tLiver\tNo\tE. bieneusi (JN107808)\tChr-2R, PCR\t\n8\t263/CZW\tF/17\tPhI/SIR, MMF (2)\tLiver\tNo\t\nG. intestinalis\n\tIFA\t\n9\t348/CZW\tF/9\tPhI/SIR (2)\tLiver\tDiarrhea weight loss 1,5 kg\tC. felis (KP675946)\tZ-N, PCR IFA—neg!\t\n10\t707/ON\tF/36\tFull (1)\tNo/celiac disease\tProlonged diarrhea\tEnterocytozoon/Encephalitozoon\tChr-2R, PCR (Bednarska et al. 2014)\t\n11\t709/ON\tM/73\tImDef. (2)\tNo/diabetes rheumatoid arthritis\tProlonged diarrhea\tEnterocytozoon/Encephalitozoon\tChr-2R, PCR (Bednarska et al. 2014)\t\n12\t718/ON\tM/33\tImDef. (1)\tNo/IBDU\tProlonged diarrhea\tEnterocytozoon/Encephalitozoon\tChr-2R, PCR (Bednarska et al. 2014)\t\n13\t757/ON\tM/31\tImDef (2)\tNo/HIV+, lymphoma\tProlonged diarrhea\t\nC. parvum\n\tZ-N, IFA, PCR\t\n14\t758/ON\tF/41\tFull (0)\tNo/intestinal disorders\tWeight loss\tB. hominis Genotype ST-3\tPCR\t\n15\t764/ON\tM/23\tSterids (1)\tNo/colitis ulcerosa\tDiarrhea/abdominal pain\tB. hominis Genotype ST-2\tPCR\t\n16\tPC1/ON\tM/35\tPhI/TAC (2)\tKidney\tDiarrhea weight loss 15 kg\tC. cayetanensis (KP642664)\tZ-N, PCR (Bednarska et al. 2015)\t\n17\tPC2/ON\tM/35\tFull (0)\tNo\tDefecation 3 times per day (no diarrhea)\tC. cayetanensis (KP642665)/B. hominis (KP675947) Genotype ST-3\tZ-N, PCR (Bednarska et al. 2015)\t\nPIC, Patient Identification Code\n\nPID, primary immunodeficiency\n\nChr-2R, smears stained by Chromotrope 2R method\n\nZN, smears stained by Ziehl-Neelsen method\n\nIFA, MerIFluor Cryptosporidium/Giardia method\n\nPCR, PCR with sequencing\n\nTAC, tacrolimus\n\nSIR, sirolimus\n\nRA, rheumatoid arthritis\n\nMMF, mycophenolate mofetil\n\nMA, mycophenolic acid\n\nDF, deflazacort\n\nImDef, other immunodeficiency (no transplant, no PID)\n\nDI, degree of immunodeficiency\n\nPhI, pharmacology immunodepression\n\n\n\nThe patients were infected with different Cryptosporidium species (1.4%, n = 4), Giardia intestinalis (0.7%, n = 2), C. cayetanensis (0.7%, n = 2), B. hominis (1%, n = 3), and presented with microsporidian invasion (n = 4). In one case, coinfection with Cyclospora and Blastocystis was detected (Table 2). The prevalence of pathogens was found in both immunocompetent (6.5%) and immunocompromised patients (4.6%). Micropathogen infections in children (< 18 years old, n = 221) and adults (> 18 years old, n = 62) were 3.2 and 12.9%, respectively (p = 0.226) (Table 3). There were significant differences in the prevalence of parasitic Protista (Cryptosporidium, Giardia, Cyclospora) between the male (5%) and female (0.6%) groups (p = 0.015, df = 1, χ2 = 5.885). The prevalence of Apicompexa infection with Cryptosporidium or Cyclospora species was significantly associated with diarrhea and heavy immunodeficient patients (p = 0.002, df = 2, χ2 = 12.88). There was an interesting link between micropathogen infections and immunosuppressed rates (p = 0.044, df = 2, χ2 = 6.242). Most parasitic infections were reported in patients with severe, second-stage immunodeficiency (6.1%), while in patients with mild or no immunosuppression, it was 0.6 and 2.2%, respectively.Table 3 Prevalence of protozoan parasitic infections (Cryptosporidium, Giardia, Blastocystis, microsporidia) detected in patients of varying age and detection methods (PCR and microscopy)\n\nPatients\t% (total/infected)\t% (children/infected)\t% (adult/infected)\t\nParasites\t\nCryptosporidium spp.\t1.4 (241/4)\t3.6 (221/3)\t1.6 (64/1)\t\n\nGiardia intestinalis\n\t0.7 (241/2)\t0.9 (221/2)\t0 (64/0)\t\n\nBlastocystis hominis\n\t1.2 (249/3)\t0 (187/0)\t4.7 (64/3)\t\nMicrosporidia Enterocytozoon/Encephalitozoon\t1.2 (209/4)\t0 (147/0)\t6.3 (64/4)\t\nTotal\t4.6 (285/13)\t2.3 (221/5)\t12.5 (64/8)\t\n\n\nCryptosporidium infections\nIn our study, infections with Cryptosporidium occurred in four patients with diarrhea and heavy immunodeficiency. Among the four detected cases, three different species of Cryptosporidium were identified by PCR assay. Only one HIV+ adult patient (756/ON) was infected with C. parvum. Two prolonged infections in patients with PID (9/CZW, 17/CZW) were caused by C. meleagridis and Cryptosporidium spp., respectively (partially described by Wolska-Kusnierz et al. 2007). The infection caused by C. felis was detected in the liver transplant girl.\n\nOur long-term study on two patients with prolonged cryptosporidiosis and heavy disorders was partially described by Wolska-Kusnierz et al. (2007). We reported the results of parasitological study, which was in progress for 7 years from 2007 to 2011–2014. Patient no. 9/04 infected with C. meleagridis underwent a four-time transplant in 2006 and, 6 years after transplantation with full immune reconstitution and no parasite infection, is alive and well. All results were obtained by three methods: ZN, IFA, and PCR—which at this time tested negative for Cryptosporidium.\n\nPatient no. 17/05 with CD40 ligand deficiency complicated by cholangitis scleroticans and Cryptosporidium infection revealed Cryptosporidium infection at the age of 5, but long-term azithromycin treatment did not clear up or treat the infection. At age 7, he received matched unrelated stem cell transplantation. Liver failure with vanishing bile duct syndrome in the course of severe graft versus host disease (GVHD) occurred after transplantation. In March 2008, liver transplantation from an unrelated donor was successfully performed. In a follow-up study, we observed the clearance of Cryptosporidium infection together with full immune reconstitution. No recurrence of parasite infection was detected during the following 7 years of observation.\n\nBlastocystis hominis infection\nA partially retrospective study regarding B. hominis was carried out on 249 patients (187 minors). Positive PCR results were obtained only from adult patients (4.7%, 3/64), two of which were hospitalized. The 23-year-old male suffered from colitis ulcerosa, infections with Cytomegalovirus (CMV), and Clostridium difficile. The 41-year-old female complained of intestinal disorders, such as abdominal pain, weight loss, and alternating rhythm of bowel movements. The third patient (PC2), infected with Blastocystis, was first diagnosed with C. cayetanensis. Coinfection with Blastocystis was detected based on the molecular study. Three defecations per day were reported as a physiological norm by this immunocompetent male (Bednarska et al. 2015).\n\nDNA sequence alignments and phylogenetic analysis were conducted using MEGA version 6.0. Two isolates from 758/ON and PC2/ON patients were closely related (identical), and both were grouped in the region (III) closely related to human isolates. The nucleotide sequences of the ITS fragment of DNA isolated from patient no. 764/ON were also related to genotypes rarely isolated from human specimens (region II) (Abe 2004). The relatedness of isolates, grouped by its sequence identity, is showed in the phylogenetic tree (Fig. 1). The GenBank accession numbers assigned to the sequences determined in this study are as follows: genotype 758/ON, MG905018, genotype 764/ON, MG905016, and genotype PC2/ON, MG905017.Fig. 1 Evolutionary relationships of taxa. The evolutionary history was inferred using the Neighbor-Joining method. The percentage of replicate trees in which the associated taxa clustered together in the bootstrap test (1000replicates) is shown next to the branches. The tree is drawn to scale, with branch lengths in the same units as those of the evolutionary distances used to infer the phylogenetic tree. The evolutionary distances were computed using the Kimura2 parameter method and are in the units of the number of base substitutions per site. The analysis involved 51 nucleotide sequences. All positions containing gaps and missing data were eliminated. There were a total of 398 positions in the final data set. Evolutionary analyses were conducted in MEGA6\n\n\n\nDiscussion\nPrevalence of micro-parasitic infection\nMicroparasites, such as viruses and bacteria, may cause infective diarrhea in immunodeficient and post-transplant patients in endemic areas, yet the data regarding such infections in Poland are scarce (Table 4). The research presented here represents one of few studies of the incidence, disease manifestation, management, and outcome of microparasitic infection in transplant recipients and immunocompromised individuals. This study indicates that protozoan parasitic infections are rare among immunodeficient patients in Poland. The overall prevalence of micro-pathogens in the study participants was 4.6%, and it was three times higher in adults (12.5%) than in children (2.3%), which attests to the fact that microparasitic infections are the most frequent in patients who are not minors. Accordingly, adult patients tested positive mainly for Blastocystis and microsporidia, while children were more often infected with the Cryptosporidium species. It is worthy of attention that Cryptosporidium parasites, together with G. intestinalis, were included in the WHO’s “Neglected disease initiative” in 2004 (Savioli et al. 2006) due to their significance in public health.Table 4 Prevalence of Cryptosporidium spp., Giardia intestinalis, Blastocystis hominis, microsporidia Enterocytozoon/Encephalitozoon in human using different (microscopic/IFA/PCR) methods in Poland, 2000–2017\n\nParasite species\tN positive/N total\tImmunological/medical status\tStudy period\tDiagnostic method\tReferences\t\n\nCryptosporidium spp.\n\t9/221\tImmunocompetent with diarrhea\t2013–2017\tLM\tKłudkowska et al. (2017)\t\n36/246\tImmunocompetent with diarrhea\t2006\tLM (ZN)\nIFA, PCR\tRożej et al. (2010)\t\n1/35\tPIDs\t2002–2007\tBajer et al. (2008); Wolska-Kusnierz et al. (2007)\t\n\nCryptosporidium parvum\n\t9/35\tImmunocompetent/PIDs\t\n\nC. hominis\n\t1/35\tPIDs\t\n\nC. meleagridis\n\t1/35\tPIDs\t\n1\tHIV\tnd\tLM (ZN), PCR\tWesołowska et al. (2016)\t\n\nCryptosporidium felis\n\t1\tLiver transplant\t2014\tLM (ZN), PCR\tThis paper\t\n\nGiardia intestinalis\n\t3/232\tImmunocompetent\tnd\tLM(DS, TS) PCR\tSolarczyk et al. (2010)\t\n2/285\tImmunocompetent/transplant recipient\t2007–2016\tIFA\tThis paper\t\n6/913\tImmunocompetent\t2008–2010\tLM (DS)\tDuda et al. (2015)\t\n\nCyclospora cayetanensis\n\t2/2\tRenal transplant/immunocompetent\t2015\tLM (ZN), PCR\tBednarska et al. (2015)\t\n3/221\tImmunocompetent with diarrhea\t2013–2017\tLM\tKłudkowska et al. (2017)\t\n\nBlastocystis hominis\n\t3/249\tImmunocompetent/transplant recipient/medical suppression\t2007–2016\tPCR\tThis paper\t\n140/913\tImmunocompetent\t2008–2010\tLM (DS)\tDuda et al. (2015)\t\n\nEnterocytozoon bieneusi\n\t1/60\tLiver transplant recipient\t2011\tPCR\tBednarska et al. (2013)\t\nEnterocytozoon/Encephalitozoon\t10/80\tImmunocompetent/PIDs/transplant recipient\t2002–2008\tLM (TS), PCR\tBednarska et al. (2014)\t\n\nEnterocytozoon bieneusi\n\t7/86\tRenal transplant recipients\t2013–2015\tMS, PCR\tKicia et al. (2014)\t\n\nEncephalitozoon cuniculi\n\t15/86\t\nLM, light microscopy; ZN, Ziehl-Neelsen stain; JM, culture on Jones medium; DS, direct smear; TS, trichrome stain\n\n\n\nDetection and characterization of Cryptosporidium spp. and Blastocystis spp. isolates\nIt is known from earlier studies that cryptosporidiosis prevalence varies from 1 to 5% in children from developed countries and 50% in children from developing countries. Cryptosporidiosis can be found more often in young children and immunocompromised patients (especially those with HIV-associated immunosuppression) than in a healthy adult population (Cheng et al. 2005).\n\nIn our study, the Cryptosporidium species was detected in 3.6% of children, which is similar to the 1.2% in the Teheran study (Tahvildar-Biderouni and Salehi 2014), 2% in Poland (Solarczyk et al. 2010) 3.9% of the Cryptosporidium-infected children in the study of Tanzania (Tellevik et al. 2015), 4.6% in Ethiopia (de Lucio et al. 2016), and 2.4% Iranian children (Taghipour et al. 2011). Cryptosporidium prevalence found in this study is lower than that reported for children with diarrhea in Canada which was at 15.7% (Iqbal et al. 2015), 10.4% in Tanzania, and 15.1% in Qatar (Boughattas et al. 2017). These variations could be explained by the differences in the region of study, the hygiene practices, as well as the socio-economic status of participants involved in the studies.\n\nBy using molecular methods in this study, C. parvum, C. meleagridis, and C. felis were identified in diarrheic patients. All identified Cryptosporidium isolates are considered as zoonotic species which are commonly reported in humans and wildlife worldwide (Xiao 2010).\n\nThe distribution of Cryptosporidium species in humans varies across geographic areas and socioeconomic conditions (Chalmers and Katzer 2013). In European countries, the detection of infection with C. parvum, C. hominis, and C. meleagridis in humans increased. Infections with C. canis and C. felis are reported in studies conducted in developing countries (Xiao 2010).\n\nIn our study, two cases of chronic cryptosporidiosis (C. meleagridis and Cryptosporidium sp.) were reported among PID children. Hyper-IgM patients with C. meleagridis infection (partially reported by Wolska-Kusnierz et al. 2007) were monitored after four bone marrow transplantations (the last one performed in 2006), and the problem with cryptosporidiosis was resolved. Within a few years, no relapse to Cryptosporidium infection was observed. The resolution of opportunistic infections in immune-suppressed patients requires the restoration of mucosal immunity, usually achieved following the discontinuation of immunosuppressive drugs (Nachbaur et al. 1997). The patient diagnosed with CD40 ligand deficiency, sclerosis cholangitis, and prolonged cryptosporidiosis required bone marrow transplant as well as liver transplant after GVHD intended for the full immune reconstruction. Chronic cryptosporidiosis can cause GVHD after stem cell transplantation, thus requiring a reduction of immunosuppressive drugs and a specific therapy, whereas GVHD requires intensification of immunosuppression (Legrand et al. 2011; Washington and Jagasia 2009). Presumably, in the case in question, the heavy immunosuppression led to re-development of cryptosporidiosis. Relapse to cryptosporidiosis at this stage of treatment can be dangerous for the health and life of a patient. Therefore, control and prompt diagnosis of intestinal cryptosporidiosis are recommended.\n\nCryptosporidium felis has a visibly more restricted host range than C. parvum and, using molecular techniques, it has been confirmed that it may infect cats (Lucio-Forster et al. 2010), immunocompetent and immunocompromised humans (Cacciò et al. 2002), as well as cattle (Bornay-Llinares et al. 1999). Infection with C. felis was detected in a young female who had undergone a liver transplant. Importantly, this patient resided in a rural environment with direct access to dogs, cats, and other farm animals. The most probable source of infection comprised cats from the close surroundings. In children from developing countries, C. felis is responsible for as much as 3.3% of all cryptosporidiosis cases (Lucio-Forster et al. 2010).\n\nCryptosporidium infections were detected aided by microscopic studies, using Ziehl-Neelsen staining and the IFA method, while the species identification was confirmed using PCR. Interestingly, in this case, C. felis infection was not detected in immunofluorescent testing dedicated to detection of a wide range of Cryptosporidium species in stool specimens. These results suggest that studies on the transmission of zoonotic species are difficult due to the lack of suitable subtyping tools for the distinction of Cryptosporidium spp. (Ryan et al. 2014). Given the above, it is necessary that two different methods for the detection of Cryptosporidium and other parasitic infections in humans are employed. A diagnosis based only on a microscopic or immunofluorescent test or molecular methods only may lead to false-negative results. A molecular study is necessary to recognize the genotype and subtype of Cryptosporidium and to identify the organism responsible for infection along with the source and routes of transmission.\n\nInfection with Blastocystis has been reported as asymptomatic, acute, or chronic symptomatic (Windsor et al. 2002; Tan 2004). This wide range of responses to infection could be related to genetic diversity. Blastocystis hominis was detected only in adult patients (4.7%), and in one male patient, co-infection with C. cayetanensis was found. In this study, the pathogen was detected only by molecular methods. An earlier study of patients with hematopoietic and lymphoid hyperplastic diseases (not published) compared light microscopy, immunofluorescence, ELISA, cultivation using Joni’s medium, and PCR as methods used for detection of Blastocystis sp. The most useful diagnostic methods seem to be cultivation (15%, 6/40) and PCR (17.5%, 7/40). Parasites were detected in 30% of patients using both above-mentioned methods. These results confirm that two diagnostic methods should be used in parasitological diagnostic.\n\nThe sources of infection with Blastocystis can be water or zoonotic transmission (Abe 2004), while the risk factors include immunocompromised health (Rao et al. 2003) or poor hygiene practices (Nimri and Meqdam 2004; Tan 2004). Pathogenicity of Blastocystis is controversial and still undefined. Thus, further research should be carried out to determine the potential risk associated with the invasiveness of their subtypes. The most dominant subtypes in humans are subtype 3 (41.7 to 92.3%) and subtype 1 (7.7 to 25%), followed by either subtype 6 (10 to 22.9%), subtype 2 (1.3 to 32.1%), or subtype 4 (1.3 to 37.5%)—the occurrence of which is associated with geographical distributions. In most studies, other genotypes (ST5, ST7–9) were identified at lower frequencies globally (Tan 2004; Alfellani et al. 2013). In our study, subtype 2 was detected in immunodeficient patients with colitis ulcerosa and co-infections with CMV and C. difficile. Subtype ST-3 was diagnosed in two immunocompetent patients, one of which was hospitalized due to weight loss and alternating rhythm of bowel movements. The other one was diagnosed with co-invasion during the prolonged, asymptomatic infection with C. cayetanensis (Bednarska et al. 2015). It is difficult to assess the impact of B. hominis infection on the chronic C. cayetanensis infection. The higher frequency of defecations in this patient could have been a symptom of irritable bowel caused by Blastocystis. Further research must be conducted to clarify the effects of B. hominis on intestinal peristalsis, asymptomatic C. cayetanensis infection, or any different microparasitic infection which may result in prolonged contamination of the environment by asymptomatic, but chronically infected patients.\n\nDiarrhea in immunodeficiency\nA majority of diarrhea cases were due to non-parasitic infections. In total, 35% patients had symptoms at the time of the survey. Gastrointestinal symptoms were more often reported in children with PID (65%) and adult patients (84%). Post-transplant diarrhea is a common and distressing occurrence in patients, which can have significant deleterious effects on the clinical course and well-being of organ recipients. The true incidence of diarrhea in liver transplant recipients is unknown but possibly ranges from 10 to 43%—according to published studies in other solid organ and bone marrow transplantation (Azami et al. 2010; Galván et al. 2011; Agholi et al. 2013). Our observations did not agree with these data. In our study on liver transplant recipients, only 2% were infected with parasites, but diarrhea was occasionally presented (4%). Diarrhea could be a frequent side effect of immunosuppressive medications (mycophenolate mofetil (MMF), cyclosporine A (CSA), tacrolimus, and sirolimus) or an additional infectious agent, including viruses (e.g. Cytomegalovirus), bacteria, or fungi (e.g. C. difficile) (Bonatti et al. 2012; Song et al. 2006; Dave et al. 2014). More than half of the patients tested in this study had heavy immunodeficiency due to medications or diseases such as inflammatory bowel disease (e.g., colitis ulcerosa) or celiac disease, and probably these factors were the main reasons for intestinal disorders.\n\nIn conclusion, the current study illustrates the need to maintain a high index of suspicion for microparasites, especially Cryptosporidium, microsporidia, and Blastocystis in immunodeficient or transplant patients who present prolonged diarrhea. We diagnosed Cryptosporidium and Cyclospora species (both Apicomplexa) as the main cause of heavy parasitic diarrhea. In our opinion, parasitic infections should be diagnosed with two different methods for an accurate diagnosis. Probably, the routine stool evaluations for parasites may not identify rare zoonotic species or low intensity of parasites. Furthermore, our results imply that a molecular analysis used to identify the parasite species should be performed as soon as the zoonotic Cryptosporidium infection is suspected. Various other etiologies, including inflammatory bowel disease, must be considered in the differential diagnosis. This will allow choosing the proper treatment for specific parasite infections.\n\nThis study was partially supported by the Ministry of Science and Higher Education in Warsaw, Poland (Grant No. N N404101036).\n\nEthics approval\nWritten informed consent was obtained from all patients or guardians of minor patients, and the study protocol followed ethical guidelines of the 2013 Declaration of Helsinki. All approvals for the study have been obtained according to Polish regulations.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\nAbe N Molecular and phylogenetic analysis of Blastocystis isolates from various hosts Vet Parasitol 2004 120 235 242 10.1016/j.vetpar.2004.01.003 15041098 \nAgholi M Hatam GR Motazedian MH Microsporidia and coccidia as causes of persistence diarrhea among liver transplant children: incidence rate and species/genotypes Pediatr Infect Dis J 2013 32 185 187 10.1097/INF.0b013e318273d95f 22982981 \nAlfellani MA Jacob AS Perea NO Krecek RC Taner-Mulla D Verweij JJ Levecke B Tannich E Clark CG Stensvold CR Diversity and distribution of Blastocystis sp. subtypes in non-human primates Parasitology 2013 140 966 971 10.1017/S0031182013000255 23561720 \nAnane S Attouchi H Microsporidiosis: epidemiology, clinical data and therapy Gastroenterol Clin Biol 2010 34 450 464 10.1016/j.gcb.2010.07.003 20702053 \nAzami M 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The enteric opportunistic infections working group N Engl J Med 1992 16 161 166 10.1056/NEJM199201163260304 \nWesołowska M Szostakowska B Kicia M Sak B Kvac M Knysz B Cryptosporidium meleagridis infection: the first report in Poland of its occurrence in an HIV-positive woman Ann Parasitol 2016 62 239 241 27770764 \nWindsor JJ Macfarlane L Hughes-Thapa G Jones SA Whiteside TM Incidence of Blastocystis hominis in faecal samples submitted for routine microbiological analysis Br J Biomed Sci 2002 59 154 157 10.1080/09674845.2002.11783653 12371057 \nWolska-Kusnierz B Bajer A Caccio S Heropolitanska-Pliszka E Bernatowska E van Dongen J Bednarska M Paziewska A Siński E Cryptosporidium infection in patients with primary immunodeficiency syndromes J Pediatr Gastroenterol Nutr 2007 45 458 164 10.1097/MPG.0b013e318054b09b 18030213 \nXiao L Molecular epidemiology of cryptosporidiosis: an update Exp Parasitol 2010 124 80 89 10.1016/j.exppara.2009.03.018 19358845 \nXiao L Escalante L Yang C Sulaiman I Escalante AA Montali RJ Fayer R Lal AA Phylogenetic analysis of Cryptosporidium parasites based on the small-subunit rRNAgene locus Appl Environ Microbiol 1999 65 1578 1583 10103253\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0932-0113",
"issue": "117(9)",
"journal": "Parasitology research",
"keywords": "Blastocystis hominis; C. felis; Cryptosporidium spp.; Diarrhea; Opportunistic parasites; PID patients",
"medline_ta": "Parasitol Res",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000293:Adolescent; D000328:Adult; D000818:Animals; D016844:Blastocystis; D016776:Blastocystis Infections; D002648:Child; D003457:Cryptosporidiosis; D003458:Cryptosporidium; D021744:Cyclospora; D021866:Cyclosporiasis; D003967:Diarrhea; D005243:Feces; D005260:Female; D005872:Giardia; D005873:Giardiasis; D006801:Humans; D007411:Intestinal Diseases, Parasitic; D008297:Male; D016814:Microsporidia; D016881:Microsporidiosis; D008875:Middle Aged; D009894:Opportunistic Infections; D011044:Poland; D015995:Prevalence; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "8703571",
"other_id": null,
"pages": "2869-2879",
"pmc": null,
"pmid": "29946765",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article",
"references": "26095244;20428648;21325545;16878265;28575116;24080063;8815125;19303009;14621046;29111140;23982239;9684328;24051931;18030213;19524102;24959769;19119509;22340660;18826821;20729925;20499657;20702053;15214876;21692958;16148530;23891667;12371057;16457493;18301922;11193609;1370122;15041098;19545515;23772577;12967491;18666410;16046184;24523472;17004098;22810017;16545611;26249024;10103253;22982981;10103236;23566713;25732683;11749756;22347312;28682780;15703615;15023017;9431916;23561720;20176507;9208124;24041484;16145337;19358845;27466809;26452235;27770764;24834304;15859939;20707303;15567582;25111501;28824878;21075531",
"title": "Prevalence of Cryptosporidium, Blastocystis, and other opportunistic infections in patients with primary and acquired immunodeficiency.",
"title_normalized": "prevalence of cryptosporidium blastocystis and other opportunistic infections in patients with primary and acquired immunodeficiency"
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"abstract": "Bacillus Calmette-Guérin (BCG) unresponsive/relapsing patients with non-muscle invasive bladder cancer (NMIBC) who prefer bladder preservation over radical cystectomy (RC) or those who do not qualify for surgery may be offered intravesical therapies. Gemcitabine (GEM) combined with Docetaxel (DOCE) has been offered at Johns Hopkins Hospital (JHH).\nTo evaluate experience with GEM/DOCE, to confirm safety of the regimen, to identify populations that may benefit most, and to consider the appropriate endpoints for judging efficacy of second line therapies.\nThirty-three patients who received full induction GEM/DOCE since 2011, per the protocol adapted from U. Iowa, were identified and characterized. Multivariable logistic regression was used to determine factors associated with recurrence. Cox proportional hazard models evaluated risk factors for disease-free survival (DFS) and high-grade recurrence-free survival (HG-RFS).\nThere were no serious adverse effects of therapy. Across all patients, median follow-up time was 18.6 months with a median DFS of 6.5 months, 42% 1-year, and 24% 2-year DFS. Median HG-RFS was 17.1 months with 56% 1-year and 42% 2-year HG-RFS. Among patients initially presenting with HG-NMIBC, 46% (13/28) had HG recurrence. BCG unresponsive/relapsing patients (N = 25) displayed 49% 1-year HG-RFS and 34% 2-year HG-RFS. In total, there were 5 LG and 16 HG recurrences, with 5 progressions and 8 cystectomies among these.\nGEM/DOCE is a well-tolerated therapy that deserves further study as an alternative to immediate RC for highly selected patients with HG-NMIBC. BCG naïve patients responded more effectively than BCG unresponsive/relapsing patients. As anticipated, GEM/DOCE efficacy was improved for HG only patients.",
"affiliations": "The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.;The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.;The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Universita Vita-Salute San Raffaele, Milan, Italy.;The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Department of Urology, Albert Einstein College of Medicine, Bronx, NY, USA.;The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Department of Urology, Albert Einstein College of Medicine, Bronx, NY, USA.;The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.",
"authors": "Milbar|Niv|N|;Kates|Max|M|;Chappidi|Meera R|MR|;Pederzoli|Filippo|F|;Yoshida|Takahiro|T|;Sankin|Alexander|A|;Pierorazio|Phillip M|PM|;Schoenberg|Mark P|MP|;Bivalacqua|Trinity J|TJ|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.3233/BLC-170126",
"fulltext": "\n==== Front\nBladder CancerBladder CancerBLCBladder Cancer (Amsterdam, Netherlands)2352-37272352-37352352-3727IOS Press Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands BLC17012610.3233/BLC-170126Research ReportOncological Outcomes of Sequential Intravesical Gemcitabine and Docetaxel in Patients with Non-Muscle Invasive Bladder Cancer N. Milbar et al.Oncological Outcomes of Sequential Intravesical GEM/DOCEMilbar Niv a*Kates Max aChappidi Meera R. aPederzoli Filippo bYoshida Takahiro aSankin Alexander cPierorazio Phillip M. aSchoenberg Mark P. cBivalacqua Trinity J. a\na The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA\n\nb Universita Vita-Salute San Raffaele, Milan, Italy\n\nc Department of Urology, Albert Einstein College of Medicine, Bronx, NY, USA\n* Correspondence to: Niv Milbar, The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins University School of Medicine, 1800 Orleans Street, Marburg 134, Baltimore, MD 21287, NY, USA. E-mail: nmilbar1@jhmi.edu.27 10 2017 2017 3 4 293 303 © 2017 – IOS Press and the authors. All rights reserved2017This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nBacillus Calmette-Guérin (BCG) unresponsive/relapsing patients with non-muscle invasive bladder cancer (NMIBC) who prefer bladder preservation over radical cystectomy (RC) or those who do not qualify for surgery may be offered intravesical therapies. Gemcitabine (GEM) combined with Docetaxel (DOCE) has been offered at Johns Hopkins Hospital (JHH).\n\nObjective:\nTo evaluate experience with GEM/DOCE, to confirm safety of the regimen, to identify populations that may benefit most, and to consider the appropriate endpoints for judging efficacy of second line therapies.\n\nMethods:\nThirty-three patients who received full induction GEM/DOCE since 2011, per the protocol adapted from U. Iowa, were identified and characterized. Multivariable logistic regression was used to determine factors associated with recurrence. Cox proportional hazard models evaluated risk factors for disease-free survival (DFS) and high-grade recurrence-free survival (HG-RFS).\n\nResults:\nThere were no serious adverse effects of therapy. Across all patients, median follow-up time was 18.6 months with a median DFS of 6.5 months, 42% 1-year, and 24% 2-year DFS. Median HG-RFS was 17.1 months with 56% 1-year and 42% 2-year HG-RFS. Among patients initially presenting with HG-NMIBC, 46% (13/28) had HG recurrence. BCG unresponsive/relapsing patients (N = 25) displayed 49% 1-year HG-RFS and 34% 2-year HG-RFS. In total, there were 5 LG and 16 HG recurrences, with 5 progressions and 8 cystectomies among these.\n\nConclusions:\nGEM/DOCE is a well-tolerated therapy that deserves further study as an alternative to immediate RC for highly selected patients with HG-NMIBC. BCG naïve patients responded more effectively than BCG unresponsive/relapsing patients. As anticipated, GEM/DOCE efficacy was improved for HG only patients.\n\nKeywords Urinary bladder neoplasmsbladderdocetaxelgemcitabine\n==== Body\nINTRODUCTION\nBacillus Calmette-Guérin (BCG) following transurethral resection of bladder tumor (TURBT) remains the standard of care for patients diagnosed with intermediate and high risk non-muscle invasive bladder cancer (NMIBC) [1, 2]. After BCG, 30–77% of patients will experience recurrence within 5 years [3–5]. The standard of care for patients with high risk BCG-unresponsive NMIBC is radical cystectomy (RC) or additional intravesical BCG or chemotherapy. Some patients are not ideal candidates for surgery due to co-morbidities, while others may qualify for surgery but prefer bladder preservation, while others may lack access to BCG –all of these patients may consider alternative intravesical therapies. However, significant trade-offs exist for patients, namely the risk of progression associated with delaying or avoiding RC versus the potential morbidities and mortality associated with RC [6–8]. These considerations are part of the decision-making process that patients and physicians must undertake.\n\nIn the search for less invasive alternatives to RC, combinations of second-line intravesical chemotherapeutic agents have been assessed, including mitomycin C (MCC), valrubicin, gemcitabine, and docetaxel. Gemcitabine, a deoxycytidine nucleoside analog, has been shown to have antitumoral effect in both metastatic and NMIBC [9, 10]. Phase 2 trials in patients with BCG refractory/unresponsive disease have reported recurrence free-survival of up to 28% at 1 year [11]. Docetaxel, a microtubule depolymerization inhibitor, has shown antitumor efficacy in breast, prostate, and urothelial cancers [12]. In one study, fifty-four patients with BCG-refractory NMIBC were followed for a median of 39.1 months and found to have a 40% 1 year recurrence free survival [13, 14]. Despite this, the urological community continues to lack consensus regarding appropriate expectations from potential new therapies in the face of a curative option available with RC.\n\nIn 2015, Steinberg et al. published the first known study of sequential gemcitabine and docetaxel (GEM/DOCE) as salvage therapy for NMIBC patients who failed BCG, and demonstrated a 54% 1-year and 34% 2-year recurrence free survival, in addition to a 66% complete response at first surveillance [15]. At our institution, GEM/DOCE has been administered following the treatment protocol established by Steinberg et al. [15]. Our objective was to report our institutional experience with sequential gemcitabine and docetaxel for patients with NMIBC and to report on the regimen’s safety. Further, we examined the question of which endpoints are most appropriate for NMIBC patients receiving intravesical therapy after stratifying based on initial pathology and clinical characteristics.\n\nMATERIALS AND METHODS\nApproval of this research was secured from the Johns Hopkins Medicine Institutional Review Board as part of broader approval for studying perioperative and oncologic outcomes in cancers of the urinary tract in patients followed in the Johns Hopkins Cancer Registry.\n\nPatient cohort\nPatients receiving sequential Gemcitabine and Docetaxel (GEM/DOCE) were identified (N = 33) and retrospectively reviewed from the Johns Hopkins Non-Muscle Invasive Bladder Cancer database. Briefly, this database contains patients who received induction courses of intravesical therapy for NMIBC at Johns Hopkins Hospital between 2003 –2016.\n\nStudy variables\nClinicopathologic variables were collected from patient medical records. Collected variables included age at time of GEM/DOCE initiation, sex, race, smoking status, therapy initiation/end dates, previous NMIBC therapy history, surgeon responsible for care, American Joint Committee on Cancer TNM staging before GEM/DOCE induction (clinical stage), intolerance symptoms, follow-up dates and methods through entire study period, pathologic stage if follow-up biopsy obtained, American joint Committee on Cancer TNM staging at time of RC (pathologic stage) if obtained, and date/reasons for mortality.\n\nGEM/DOCE instillation\nTreatment protocol at our institution is based on the protocol established by Steinberg in collaboration with investigators at the University of Iowa, including O’Donnell and Nepple [15]. GEM/DOCE induction is given intravesically in sequential order once a week for six consecutive weeks. One gram of gemcitabine in 50 ml of sterile water is slowly instilled into the bladder and the catheter is clamped for 60 minutes. The bladder is then drained and 37.5 mg of docetaxel in 50 ml of NSS is slowly instilled in the bladder. The catheter is again clamped for 60 minutes. The docetaxel is then drained and catheter removed and the patient is questioned regarding discomfort, instructed to remain well-hydrated and to notify a physician with any adverse reactions, questions, or concerns.\n\nMaintenance BCG for recurrent Ta, T1, and CIS NMIBC has been associated with significantly longer recurrence-free survival times than induction without maintenance [16]. A recent review in European Urology recommended at least a 3 year maintenance protocol for patients who have received BCG [17]. However, since GEM/DOCE remains an experimental approach to treating recurrent NMIBC patients, no protocol has been established for maintenance therapy. Since this study spans many years, is retrospective by nature, and patients were followed by several physicians, there was no standard protocol in place for patients to receive maintenance therapy at our institution. 7/33 (21%) of patients received some form of maintenance GEM/DOCE, namely intravesical GEM/DOCE monthly between cystoscopic exams. In an ideal future randomized study, a maintenance protocol would be emphasized as part of the treatment process and currently at our institution patients receive monthly intravesical GEM/DOCE.\n\nStatistical analysis\nThe dual purpose of this study was to validate the safety of this protocol and to establish precedence for further study of the protocol in future controlled prospective studies. This was to be established by analyzing recurrence and progression rates.\n\nThe primary recurrence endpoints of interest were high-grade recurrence and any-grade recurrence. High-grade recurrence was defined as the finding of high-grade papillary carcinoma (HgTa), carcinoma in-situ (Tis), lamina propria invasion (T1), and any progression beyond these as diagnosed by tissue biopsy within 6 months of GEM/DOCE induction completion. Any-grade recurrence included recurrence with low-grade papillary carcinoma (LgTa) in addition to all previously defined high-grade recurrence. Progression included patients found to have muscle-invasive lesions (T2), invasion beyond bladder tissue (T3/T4), or metastatic disease by tissue biopsy, RC pathology, or imaging. Univariable and multivariable logistic regression was performed to determine clinical predictors (age, race, sex, pathological stage, method of follow-up, and history of BCG) of recurrence. Pathological stage was used as a surrogate for clinical tumor grade as previous studies have demonstrated high correlation between these characteristics [18, 19].\n\nNext, univariable and multivariable Cox proportional hazards modeling was performed to determine predictors of high-grade recurrence free survival (HG-RFS) and disease-free survival (DFS). Patients were stratified by BCG history (unresponsive/relapsing vs. naïve) in order to separately assess these populations. Further, patients were grouped by whether they experienced high-grade recurrence and Kaplan-Meier curves with Wilcoxon tests were generated to assess for statistical differences in HG-RFS using STATA version 14 supported by the Johns Hopkins University School of Medicine.\n\nRESULTS\nCohort background\nThe 33 patient cohort was divided among 8 (24%) patients who were naïve to BCG, 3 (9%) patients who were BCG intolerant, and 22 (66%) patients who were BCG unresponsive/relapsing as defined by the 2015 Genitourinary Cancers Symposium taskforce [20] (Fig. 1). As evidenced by the complex and variable treatment histories in Fig. 1, this was a heavily pretreated population.\n\nFig.1 Previous intravesical therapies received by order of induction courses for patients receiving GEM/DOCE.\n\nTreatment tolerance\nTwo patients who were initiated on GEM/DOCE with CIS pathology were unable to tolerate a full induction course. The first patient, who was previously BCG intolerant, received 4 weekly doses before developing hives. The patient then proceeded to receive only a one-half dose of gemcitabine and docetaxel for dose 5 and docetaxel only for dose 6. It was later determined that this patient’s reaction was likely to another medication the patient was on at the time. However, the patient did not go on to recur and eventually received a full monthly maintenance course of GEM/DOCE. The second patient, who was BCG unresponsive/relapsing, could not tolerate the initial instillation of the induction course and subsequently preferred to proceed directly to cystectomy, of which final pathology was TisN0.\n\nWhile only 2 patients experienced intolerance affecting treatment course, other patients experienced a wide range of mild symptoms including: LUTS (9/33, 27%), increased frequency (7/33, 21%), increased urgency (6/33, 18%), exhaustion (4/33, 12%), pain (3/33, 9%), hematuria (3/33, 9%), body flushing/erythema (2/33, 6%), limb cramps (2/33, 6%), incontinence (1/33, 3%), nocturia (1/33, 3%), general flu-like symptoms (1/33, 3%), decreased appetite (1/33, 3%) and lightheadedness (1/33, 3%). 12/33 (36%) patients experienced no symptoms throughout treatment (Fig. 2).\n\nFig.2 Prevalence of treatment symptoms experienced throughout induction courses of GEM/DOCE.\n\nTreatment surveillance\nIn total, 23/33 (70%) of patients demonstrated response at first surveillance. Following treatment completion, patients were assessed for recurrence by one of three methods. Variation in follow-up method resulted from the advent and adoption during the study period of CysView in assessing recurrence following intravesical therapies [21, 22]. At first post-induction visit, 9/33 (27%) were followed up with traditional in-office cystoscopy with a flexible scope under white light at a median of 8.7 weeks. 1/9 (11%) patient presented with a suspicious lesion and was subsequently taken to the operating room for TURBT which confirmed CIS. Patients in the second group (8/33, 24%) were evaluated in the operating room at a median follow-up of 6.7 weeks with a confirmatory biopsy and resection using only white light cystoscopy. 3/8 (38%) of these were found to have high-grade recurrence at first follow-up. The third group (14/33, 42%) was followed up at a median of 6.8 weeks in the operating room using both white and blue light, followed by immediate confirmatory biopsy and TURBT if indicated. 4/14 (29%) of these were found to have recurrence at first follow-up, with two having LgTa and two having CIS. In total, 6/33 (18%) experienced HG recurrence at first surveillance while 2/33 (6%) experienced LG recurrence. 1/33 (3%) patient was lost to follow-up immediately after therapy completion and the 1/33 (3%) patient proceeded directly to RC.\n\nBCG Naïve population\nThe distributions of demographic and baseline clinical characteristics were comparable between the BCG naïve and BCG unresponsive/relapsing populations (Table 1). The 8 BCG-naïve patients had a mean age of 71.9 years at induction initiation and were majority Caucasian (7/8, 88%) and male (6/8, 75%). 6/8 (75%) of patients had high grade disease (HgTa, HgT1, CIS). 3/8 (38%) of patients recurred after GEM/DOCE with high-grade disease (1 with CIS, 1 with HgT1, and 1 with HgT1 + CIS). 3/8 (38%) additional patients experienced LgTa recurrence.\n\nTable 1 Baseline characteristics of patients who received GEM/DOCE for NMIBC stratified by BCG status\n\n\tBCG naïve\tBCG Unresponsive/\tp-value\t\n\t\tRelapsing\t\nMean age\t71.9 (13.9)\t72.9 (10.8)\t0.83\t\nNo. of patients\t8\t25\t\nSex\t\t\t0.76\t\n Male\t6 (75%)\t20 (80%)\t\n Female\t2 (25%)\t5 (20%)\t\nRace\t\t\t0.81\t\n Caucasian\t7 (88%)\t21 (84%)\t\n Other\t1 (12%)\t4 (16%)\t\nStage\t\t\t0.30\t\n CIS alone\t0 (0%)\t10 (40%)\t\n TaLG\t2 (25%)\t3 (12%)\t\n TaHG\t3 (38%)\t6 (24%)\t\n TaHG+CIS\t1 (12%)\t3 (12%)\t\n T1HG\t2 (25%)\t2 (8%)\t\n T1HG+CIS\t0 (0%)\t1 (4%)\t\nHG/LG Path\t\t\t0.37\t\nat Initiation\t\n High-grade\t6 (21%)\t22 (79%)\t\n Low-grade\t2 (40%)\t3 (60%)\t\nThe other 2 previously BCG naïve patients who recurred with high-grade disease after GEM/DOCE went on to receive induction and maintenance BCG and remained disease free at the end of the study period.\n\nBCG Unresponsive/relapsing population\nThe BCG unresponsive/relapsing population had a mean age of 72.9 years and were also predominantly male (20/25, 80%) and Caucasian (21/25, 84%). Eighty-eight percent (22/25) had high-grade disease at GEM/DOCE initiation. For the purposes of our study, BCG intolerant patients were grouped with BCG unresponsive/relapsing patients. Fifty-two percent (13/25) of patients recurred with high-grade disease after GEM/DOCE (7 with CIS, 4 with HgTa, 2 with T1). Eight percent (2/25) of additional patients experienced LgTa recurrence. Of the BCG unresponsive/relapsing patients who recurred with high-grade disease after GEM/DOCE and then elected to again avoid cystectomy, 2 were found to have upper tract cancer, 1 was lost to follow-up, 1 received BCG and has yet to recur, and 1 was monitored with cystoscopies and has yet to recur as of the end of the study period.\n\nHigh-Grade Recurrence Free Survival (HG-RFS) and Disease-Free Survival (DFS)\nMean (SD) and median follow-up for the overall cohort were 17.6 (9.5) months and 18.6 months respectively. Fifty percent (8/16) of HG events were in the initial 6 months of follow-up. One-year HG-RFS was 56% and 1-year DFS was 42%. Two-year HG-RFS was 42% and 2-year DFS was 24% (Fig. 4, Table 3). Median DFS was 6.5 months. In total, 23/33 (70%) of patients demonstrated response at first surveillance.\n\nFig.3 Cumulative number of cystectomies of patients who received GEM/DOCE since therapy initiation.\n\nFig.4 Kaplan-Meier plots of A) HG-RFS vs. DFS B) HG-RFS by HG vs LG pathology at therapy initiation C) HG-RFS by CIS vs. No CIS at therapy initiation D) HG-RFS by BCG-naïve vs. BCG-failed at therapy initiation.\n\nTable 2 Baseline characteristics of patients who received GEM/DOCE for NMIBC stratified by recurrence status\n\n\tNo Recurrence\tLG Recurrence\tHG Recurrence\tp-value\t\nMean age\t73.0 (9.6)\t69.4 (14.6)\t73.4 (12.1)\t0.79\t\nNo. of patients\t12\t5\t16\t\nSex\t\t\t\t0.92\t\n Male\t9 (75%)\t4 (80%)\t13 (81%)\t\n Female\t3 (25%)\t1 (20%)\t3 (19%)\t\nRace\t\t\t\t0.23\t\n Caucasian\t11 (92%)\t3 (60%)\t14 (88%)\t\n Other\t1 (8%)\t2 (40%)\t2 (12%)\t\nStage\t\t\t\t0.001\t\n CIS alone\t7 (58%)\t0 (0%)\t3 (19%)\t\n TaLG\t0 (0%)\t4 (80%)\t1 (6%)\t\n TaHG\t3 (25%)\t1 (20%)\t5 (31%)\t\n TaHG+CIS\t0 (0%)\t0 (0%)\t4 (25%)\t\n T1HG\t1 (8%)\t0 (0%)\t3 (19%)\t\n T1HG+CIS\t1 (8%)\t0 (0%)\t0 (0%)\t\nHG/LG Path at Initiation\t\t\t\t<0.001\t\n High-grade\t12 (43%)\t1 (3%)\t15 (54%)\t\n Low-grade\t0 (0%)\t4 (80%)\t1 (20%)\t\nTable 3 Key recurrence/cystectomy metrics of patients who received GEM/DOCE\n\nMetric\tResult\tMetric\tResult\t\nHG-RFS among all patients\t\tHG-RFS among BCG Naïve patients\t\n Median\t17.1 months\t Median\t–\t\n 1-year\t56%\t 1-year\t75%\t\n 2-year\t42%\t 2-year\t63%\t\nDFS among all patients\t\tHG-RFS among BCG Unresponsive/\t\n\t\t Relapsing patients\t\n Median\t6.5 months\t Median\t6.5 months\t\n 1-year\t42%\t 1-year\t49%\t\n 2-year\t24%\t 2-year\t34%\t\nHG-RFS among initial HG patients\t\tCystectomies\t\n Median\t15.7 months\t Median time to\t16.1 months\t\n 1-year\t51%\t Among LG\t0\t\n\t\t presentation\t\n 2-year\t34%\t Among HG\t8 (10 rec.)\t\n\t\t presentation\t\nOf patients who initiated GEM/DOCE therapy after high-grade presentation, 1-year HG-RFS was 51% and 2-year HG-RFS was 34% (Fig. 4). For these patients, median HG-RFS was 15.7 months. Median time to high-grade event was 6.0 months. 7/15 (47%) of HG events among initially HG patients were in the initial 6 months of follow-up.\n\nBCG naïve patients had a median DFS of 6.5 months with a 50% 1-year DFS and 25% 2-year DFS while BCG unresponsive/relapsing patients had a median DFS of 6.5 months and a 1-year DFS of 38% and 2-year DFS of 24%. BCG naïve patients had a 75% 1-year HG-RFS and 63% 2-year HG-RFS while BCG unresponsive/relapsing patients had a 49% 1-year HG-RFS and 34% 2-year HG-RFS (median HG-RFS was 6.5 months).\n\nLow grade recurrences\nFifteen percent (5/33) of patients initiated therapy with LgTa disease. One patient recurred with HgTa disease at 4.6 months. This patient was then followed with serial cystoscopies and did not recur as of 18.2 months. The other 4 patients experienced LgTa recurrence at 1.9 months, 2.7 months, 5.6 months, and 10.4 months respectively. None of these patients went on to RC. Additionally, one patient who initially presented with HgTa went on to have LgTa at 13.2 months of follow-up.\n\nClinical predictors of recurrence\nThe baseline characteristics stratified by eventual recurrence are listed in Table 2. A total of 12 (36%) patients experienced no recurrence, 5 (15%) patients experienced LG recurrence, and 16 (54%) patients experienced HG recurrence. There was no statistical significance in age (p = 0.79), sex (p = 0.92), race (p = 0.23), smoking status (p = 0.78), or previous BCG exposure (p = 0.13). Patients who initially presented with LG disease were more likely to recur with low-grade pathology (p < 0.001) and were less likely to have CIS at therapy initiation (p = 0.042).\n\nThere were no statistically significant demographic or clinical predictors of disease recurrence (HG or LG) in multivariable logistic regression models. The same was true when using multivariable Cox proportional hazard models for predicting DFS or HG-RFS.\n\nCystectomies and progression\nAll patients who were identified for cystectomy after treatment failure had a CT scan of chest/abdomen/pelvis four weeks prior to their scheduled cystectomy date. All but two patients did not have metastatic disease. Of the 10 patients who eventually underwent cystectomy (Fig. 3, Table 4), one (10%) was BCG-naïve. This patient was initiated on GEM/DOCE after presenting with HgT1 disease post-MMC induction. Following GEM/DOCE, the patient recurred with CIS at 3.7 months, and upon workup for cystectomy, was found to have metastatic disease. The patient died from disease 5.0 months after completing GEM/DOCE.\n\nTable 4 Pathologic stage and timeline of patients who received GEM/DOCE and were recommended for RC\n\n#\tStage\tTime to RC from therapy\tTime to RC from therapy\tBCG Status\t\n\t\tinitiation (Months)\tcompletion (Months)\t\n1\tTisN0\t1.8*\t–\tU/R\t\n2\tTisN0\t4.6\t3.5\tU/R\t\n3\tTisN0\t11.2\t10.0\tU/R\t\n4\tTisN0\t14.9\t13.8\tU/R\t\n5\tT2aN0\t17.2\t15.8\tU/R\t\n6\tT3aN2\t20.4\t19.3\tU/R\t\n7\tT3aN0\t22.8\t21.7\tU/R\t\n8\tTisN0\t23.0\t21.2\tU/R\t\n9\t\tN/A; Metastatic progression\t\tNaïve\t\n10\t\tN/A; Metastatic progression\t\tU/R\t\nNote: *Patient was intolerant to GEM/DOCE and did not undergo therapy beyond first instillation; U/R = BCG unresponsive/relapsing.\n\nNine (90%) patients were BCG unresponsive/relapsing. Eight (89%) eventually underwent cystectomy while the ninth individual was found to have metastatic disease upon workup. All 9 BCG unresponsive/relapsing patients who were identified for cystectomy initiated GEM/DOCE with high-grade disease (3/10 with CIS, 3/10 with HgTa, 2/10 with HgTa+CIS, 1/10 with HgT1). Sixty-three percent (5/8) of cystectomy patients had final pathology of TisN0. One (13%) had T2a pathology and two (25%) had T3a disease, one of which was N2 (2/23 pelvic nodes positive). Median time to cystectomy from initial instillation of GEM/DOCE was 16.1 months for BCG unresponsive/relapsing patients. One additional patient was completely intolerant to GEM/DOCE and elected to proceed to RC.\n\nMortality\nAll-cause and bladder cancer-specific mortality were 3% (1/33) at 1 year and 6% (2/33) at 2 years. The first patient was found to have metastatic disease on work-up for cystectomy and passed away 5.0 months after final intravesical instillation. The second patient underwent cystectomy and experienced a parastomal hernia post-operatively and underwent hernia repair. In the immediate post-operatively period, the patient had an acute coronary event and died 22.4 months after final intravesical instillation.\n\nDISCUSSION\nSequential GEM/DOCE appears to be well tolerated in certain carefully selected patients who do not qualify for surgery due to co-morbidities or in others who prefer bladder preservation. This study primarily confirms the safety of GEM/DOCE in this population as evidenced by the lack of serious adverse events and the relative rarity of seriously concerning side-effects. It should be noted that 5 (15%) patients within the cohort progressed while on GEM/DOCE. Three (9%) patients eventually underwent cystectomy at 17.2 months (T2aN0), 20.4 months (T3aN2), and 22.8 months (T3aN0) post-GEM/DOCE initiation. Each of these patients had previously been BCG unresponsive/relapsing. The 2 (6%) remaining patients were found to have metastatic disease upon pre-operative imaging. One (3%) of these was BCG unresponsive/relapsing and the other was BCG naïve prior to GEM/DOCE. Unfortunately, the BCG naïve patient eventually died during the study period. It is well established that progression to muscle invasive bladder cancer or beyond is associated with poorer outcomes [23]. The existence of these progressions must be noted to explicitly state that GEM/DOCE therapy is not without risk. It is plausible that these patients could have been saved from progressive disease with alternative management.\n\nSecondarily, this study establishes a need for further study of this regimen in a prospective and controlled manner. This is evidenced by the greater than 50% 1-year HG-RFS and greater than 30% 2-year HG-RFS among both low-grade and high-grade patients at therapy initiation, confirming data previously published at other institutions [5, 14]. The 25 BCG unresponsive/relapsing patients in particular had a 49% 1-year HG-RFS and 34% 2-year HG-RFS with a median HG-RFS of 6.5 months. Based on the Food and Drug Administration (FDA) and American Urological Association (AUA) 2014 Public Workshop’s recommendation that therapies require a 40–50% initial complete response rate at 6 months and a durable response rate of at least 30% for 18–24 months (with the lower bound of the 95% confidence interval excluding 20%), initiating clinical trials of GEM/DOCE would appear promising in the BCG unresponsive/relapsing population [24].\n\nDFS among BCG unresponsive/relapsing patients, however, did not pass the 40–50% 1-year survival threshold (38%), 30% 2-year survival threshold (24%), or the 2-year lower bound of 20% (7%). Of note, this is higher than the 18–21% recurrence free survival of Valrubicin in the BCG failure population and in line with the 40% 1-year recurrence free survival of Docetaxel demonstrated by other studies [14]. This dichotomy between HG-RFS and DFS raises several important questions. First, should low-grade recurrence matter for 2nd-line therapies? As shown by detailed follow-up of our low-grade recurrent patients, none of these went on to need cystectomy, and moreover, none of these patients went on to have subsequent high-grade recurrence throughout the study period. We argue that low-grade recurrence should not be considered treatment failure in this population.\n\nGiven this logic, it may make sense to exclude patients with low-grade disease at GEM/DOCE initiation from the analysis to understand how treatment impacted only high-risk patients. Patients with high-grade cancer at GEM/DOCE initiation displayed a 51% 1-year HG-RFS, 34% 2-year HG-RFS, and 14% HG-RFS 2-year lower bound (<20% FDA/AUA recommendation). The only metric that fails to qualify is the 2-year lower bound of the 95% confidence interval, but much debate has centered around this recommendation [25, 26]. After publication of the thresholds by the FDA, Amrhein et al. published a response to the editor that urged the FDA/AUA panel to revisit excessive requirements that would eliminate opportunities for patients who cannot undergo a cystectomy [27]. Subsequently, the panel softened its language and stated that not all active studies are necessarily required to achieve the suggested response rates [28].\n\nFurther, we argue that 2nd line therapy studies examine alternatives to RC, such that the primary endpoint of interest should be necessity for RC or the development of metastatic disease. In our study, 18/28 (65%) high-risk patients avoided cystectomy throughout the follow-up period, and for those who underwent cystectomy or were recommended for RC, 6/10 (60%) had less than T2 disease. When looking at the BCG unresponsive/relapsing population, 16/25 (64%) of patients avoided RC. It is thus critical that the urologic community define both the type of outcomes that truly matter for NMIBC patients searching for alternatives to RC as well as the recurrence rates and endpoints that are appropriate in this population. Our study also raises the possibility that there may be a role for sequential GEM/DOCE in the BCG naïve population. Though standard of care indicates that BCG is a preferred therapy for NMIBC patients who have yet to be treated, 8/33 (24%) patients were naïve to BCG as a result of BCG shortage at the time of therapy. Three (38%) recurred with high-grade disease and 1-year and 2-year HG-RFS were 75% and 63% respectively. A previous phase II trial examining gemcitabine vs. BCG after 1 failure with BCG (as opposed to two) showed improved survival relative to gemcitabine after 2 failures and relative to BCG after 1 failure [29]. Given the continued shortage of BCG, the existence of a patient population for which BCG is not ideal (immunocompromised, genetics, etc.), and the fact that these rates are in line with success rates shown by first-line BCG, sequential GEM/DOCE may require further study as a first-line therapy [30–32]. Given the established importance of genetic susceptibility to certain treatments, an ideal future study would examine genetic expression differences between those who respond to GEM/DOCE vs. those who do not and compare this to those who respond to BCG [30, 33, 34].\n\nWith any discussion of a new therapeutic approach, the medical community must be cognizant of associated costs. At our institution, a 6-instillation induction course of Gemcitabine with Docetaxel translates to roughly 125% the cost of a 6-instillation induction course of BCG. More importantly, the regimen is significantly cheaper than other second-line therapies. For example, a 6-week course of GEM/DOCE is roughly a third of the cost of a 6-week course of Mitomycin (MMC) with Docetaxel making up the majority of that cost. Valrubicin has been shown to cost greater than $20,000 per induction course [14]. One recent study found the mean initial hospitalization cost for cystectomy to be $33,202 and mean readmission costs to be $14,417 among cystectomy patients [35]. Certainly the substantial cost savings of such an approach when addressing the most expensive cancer at a population level is important for patients, healthcare providers, and insurance companies, especially as the focus on improving the value of care provided continues to increase [36].\n\nThe limitations of this study include that it is retrospective by design. However, given the lack of consensus on clinical trial design, retrospective studies have contributed significantly to practice in the bladder cancer field. Nonetheless, the ideal controlled prospective study would assess this GEM/DOCE protocol vs. BCG as primary therapy in the high risk (HgTa, HgT1, CIS) NMIBC cohort. Additionally, the protocol should be explored for BCG unresponsive/relapsing and BCG intolerant cases in a prospective controlled manner. Another limitation is the small sample size, thereby reducing the power of any statistical analyses. As such, many potential relevant data points could not be controlled for, including comorbidities and recurrence/progression locations within the bladder. However, the study population in question is by nature one where most patients are not ideal candidates for cystectomy, indicating that there is at least some congruence in the level of morbidity within the cohort. Though we tracked the surgeon responsible for treatment, we cannot control for variations in follow-up by these physicians or variations in maintenance therapy dosing, which could have further contributed to recurrence/progression variation. In addition, we tracked history of previous intravesical therapies carefully and meticulously, but could not account for variations in history taking regarding these therapies. We therefore elected to describe a BCG unresponsive/relapsing population rather than separating this group into BCG unresponsive vs. BCG relapsing as would have been preferred by the International Bladder Cancer Group [20, 26].\n\nIn summary, intravesical Gemcitabine with Docetaxel is a well-tolerated therapy that deserves further study as an alternative to immediate RC for highly selected patients with HG-NMIBC. While admittedly patients with low-grade disease likely did not benefit from GEM/DOCE, no low-grade patients went on to cystectomy within the study period, indicating that the intervention did not cause harm. Moreover, most patients with high-grade disease who would have otherwise needed cystectomy avoided the morbid procedure. Further studies are needed to stratify the patient population that benefits most from GEM/DOCE as well as to understand whether previous intravesical therapy, maintenance regimen, follow-up methods, and other factors help explain the observed response for patients with NMIBC. Finally, the urologic community must critically re-examine appropriate outcomes and endpoints before ruling out potentially beneficial therapies for patients who have few other options.\n\nCONFLICT OF INTEREST\nThe authors have no conflict of interest to report.\n\nACKNOWLEDGMENTS\nPersky Family Award, The James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions.\n==== Refs\nREFERENCES\n[1] \n\nBurger \nM \n, \nCapoun \nO \n, \nCohen \nD \n, \nBabjuk \nM \n, \nBo \nA \n, \nHerna \nV \n, et al\nEAU Guidelines on Non–Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016 . Eur Urol \n2017 ;71 :447 –61 .27324428 \n[2] \n\nHall \nMC \n, \nChang \nSS \n, \nDalbagni \nG \n, \nPruthi \nRS \n, \nSeigne \nJD \n, \nSkinner \nEC \n, et al\nGuideline for the Management of Nonmuscle Invasive Bladder Cancer (Stages Ta, T1, and Tis): 2007 Update . J Urol \n2007 ;178 :2314 –30 .17993339 \n[3] \n\nZlotta \nAR \n, \nFleshner \nNE \n, \nJewett \nMA \n. 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Urol Oncol Semin Orig Investig \n2008 ;26 :616 –9 .\n[11] \n\nSkinner \nEC \n, \nGoldman \nB \n, \nSakr \nWA \n, \nPetrylak \nDP \n, \nLenz \nH \n, \nLee \nCT \n, et al\nSWOG S0353: Phase II Trial of Intravesical Gemcitabine in Patients with Nonmuscle Invasive Bladder Cancer and Recurrence after 2 Prior Courses of Intravesical Bacillus Calmette-Guerin . J Urol \n2013 ;190 :1200 –4 .23597452 \n[12] \n\nMackler \nNJ \n, \nPienta \nKJ \n. Drug insight: Use of docetaxel in prostate and urothelial cancers . Nat Clin Pract Urol \n2005 ;2 :92 –100 .16474654 \n[13] \n\nBarlow \nLJ \n, \nMckiernan \nJM \n, \nBenson \nMC \n. Long-Term Survival Outcomes with Intravesical Docetaxel for Recurrent Nonmuscle Invasive Bladder Cancer After Previous Bacillus Calmette-Guérin Therapy . J Urol \n2013 ;189 :834 –9 .23123371 \n[14] \n\nVelaer \nKN \n, \nSteinberg \nRL \n, \nThomas \nLJ \n, \nO’Donnell \nMA \n, \nNepple \nKG \n. Experience with Sequential Intravesical Gemcitabine and Docetaxel as Salvage Therapy for Non-Muscle Invasive Bladder Cancer . Curr Urol Rep \n2016 ;17 :1 –5 .26686192 \n[15] \n\nSteinberg \nRL \n, \nThomas \nLJ \n, \nO’Donnell \nMA \n, \nNepple \nKG \n. Sequential Intravesical Gemcitabine and Docetaxel as Salvage Therapy for Non-Muscle Invasive Bladder Cancer . Bl Cancer \n2016 ;17 :65 –72 .\n[16] \n\nLamm \nDL \n, \nBlumenstein \nBA \n, \nCrissman \nJD \n, \nMontie \nJE \n, \nGottesman \nJE \n, \nLowe \nBA \n, et al\nMaintenance Bacillus Calmette-Guerin Immunotherapy for Recurrent Ta, T1, and Carcinoma in Situ Transitional Cell Carcinoma of the Bladder: A Randomized Southwest Oncology Group Study . J Urol \n2000 ;163 :1124 –9 .10737480 \n[17] \n\nEhdaie \nB \n, \nSylvester \nR \n, \nHerr \nHW \n. Maintenance Bacillus Calmette-Guerin Treatment of Non-muscle invasive Bladder Cancer: A Critical Evaluation of the Evidence . Eur Urol \n2013 ;64 :579 –85 .23711538 \n[18] \n\nChappidi \nMR \n, \nKates \nM \n, \nJohnson \nMH \n, \nHahn \nNM \n, \nBivalacqua \nTJ \n, \nPierorazio \nPM \n. Lymph node yield and tumor location in patients with upper tract urothelial carcinoma undergoing nephroureterectomy affects survival: A U.S. population-based analysis (2004-2012) . Urol Oncol Semin Orig Investig \n2016 ;34 :331.e15 –331.e24 .\n[19] \n\nBrown \nGA \n, \nMatin \nSF \n, \nBusby \nJE \n, \nDinney \nCPN \n, \nGrossman \nHB \n, \nPettaway \nCA \n, et al\nAbility of Clinical Grade to Predict Final Pathologic Stage in Upper Urinary Tract Transitional Cell Carcinoma: Implications for Therapy . Urology \n2007 ;70 :252 –6 .17826484 \n[20] \n\nLerner \nSP \n, \nDinney \nC \n, \nKamat \nA \n, \nBivalacqua \nTJ \n, \nNielsen \nM \n, \nO’Donnell \nM \n, et al\nClarification of Bladder Cancer Disease States Following Treatment of Patients with Intravesical BCG . Bl Cancer \n2015 ;1 :29 –30 .26807434 \n[21] \n\nDaneshmand \nS \n, \nSchuckman \nAK \n, \nBochner \nBH \n, \nCookson \nMS \n, \nDowns \nTM \n, \nGomella \nLG \n, et al\nHexaminolevulinate blue-light cystoscopy in non-muscle-invasive bladder cancer: Review of the clinical evidence and consensus statement on appropriate use in the USA . Nat Rev Urol \n2014 ;11 :589 –96 .25245244 \n[22] \n\nGeavlete \nB \n, \nMultescu \nR \n, \nGeorgescu \nD \n, \nJecu \nM \n, \nStanescu \nF \n, \nGeavlete \nP \n. Treatment changes and long-term recurrence rates after hexaminolevulinate (HAL) fluorescence cystoscopy: Does it really make a difference in patients with non-muscle-invasive bladder cancer (NMIBC)? \nBJU Int \n2012 ;109 :549 –56 .21711438 \n[23] \n\nSanli \nO \n, \nDobruch \nJ \n, \nKnowles \nMA \n, \nBurger \nM \n, \nAlemozaffar \nM \n, \nNielsen \nME \n, et al\nBladder cancer . Nat Rev Dis Prim \n2017 ;3 :17022 .28406148 \n[24] \n\nJarow \nJP \n, \nLerner \nSP \n, \nKluetz \nPG \n, \nLiu \nK \n, \nSridhara \nR \n, \nBajorin \nD \n, et al\nClinical trial design for the development of new therapies for nonmuscle-invasive bladder cancer: Report of a food and drug administration and american urological association public workshop . Urology \n2014 ;83 :262 –4 .24332121 \n[25] \n\nLerner \nSP \n, \nBajorin \nDF \n, \nDinney \nCP \n, \nEfstathiou \nJA \n, \nGroshen \nS \n, \nHahn \nNM \n, et al\nSummary and Recommendations from the National Cancer Institute’s Clinical Trials Planning Meeting on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer . Bl Cancer \n2016 ;2 :165 –202 .27376138 \n[26] \n\nKamat \nAM \n, \nSylvester \nRJ \n, \nBohle \nA \n, \nPalou \nJ \n, \nLamm \nDL \n, \nBrausi \nM \n, et al\nDefinitions, End Points, and Clinical Trial Designs for Non-Muscle-Invasive Bladder Cancer: Recommendations From the International Bladder Cancer Group . J Clin Oncol \n2016 ;34 :1 –12 .26578609 \n[27] \n\nAmrhein \nJ \n, \nKamat \nAM \n, \nMorales \nA \n. Re: \nJarow \nJP \n, et al\nClinical trial design for the development of new therapies for non-muscle-invasive bladder cancer: Report of a food and drug administration and american urological association public workshop (urology 2014;83:262-265) . Urology \n2014 ;84 :494 –5 .25065995 \n[28] \n\nJarow \nJ \n, \nKluetz \nPG \n, \nLerner \nSP \n, \nLiu \nK \n, \nSridhara \nR \n, \nBajorin \nD \n, et al\nReply by the authors . Urology \n2014 ;84 :495 –6 .25065996 \n[29] \n\nDi Lorenzo \nG \n, \nPerdonà \nS \n, \nDamiano \nR \n, \nFaiella \nA \n, \nCantiello \nF \n, \nPignata \nS \n, et al\nGemcitabine versus bacille Calmette-Guerin after initial bacille Calmette-Guerin failure in non-muscle-invasive bladder cancer: A multicenter prospective randomized trial . Cancer \n2010 ;116 :1893 –900 .20162706 \n[30] \n\nZhang \nN \n, \nJiang \nG \n, \nLiu \nX \n, \nNa \nR \n, \nWang \nX \n, \nXu \nJ \n. Prediction of Bacillus Calmette-Guerin Response in Patients with Bladder Cancer after Transurethral Resection of Bladder Tumor by Using Genetic Variation Based on Genomic Studies . Biomed Res Int \n2016 ;2016 :1 –7 .\n[31] \n\nKe \nH-L \n, \nLin \nJ \n, \nYe \nY \n, \nWu \nW-J \n, \nLin \nH-H \n, \nWei \nH \n, et al\nGenetic Variations in Glutathione Pathway Genes Predict Cancer Recurrence in Patients Treated with Transurethral Resection and Bacillus Calmette-Guerin Instillation for Non-muscle Invasive Bladder Cancer . Ann Surg Oncol \n2015 ;22 :4104 –10 .25851338 \n[32] \n\nHwang \nM \n, \nBanerji \nJ \n, \nNeill \nM \n. Letter . BJU Int \n2013 ;112 :E435 –E435 .24284001 \n[33] \n\nChiong \nE \n, \nKesavan \nA \n, \nMahendran \nR \n, \nHuak \nY \n, \nHwei \nJ \n, \nKoon \nY \n, et al\nNRAMP1 and hGPX1 Gene Polymorphism and Response to Bacillus Calmette-Guerin Therapy for Bladder Cancer . Eur Urol \n2011 ;59 :430 –7 .21163569 \n[34] \n\nLima \nL \n, \nOliveira \nD \n, \nFerreira \nJA \n, \nTavares \nA \n, \nCruz \nR \n. The role of functional polymorphisms in immune response genes as biomarkers of bacille Calmette-Guérin (BCG) immunotherapy outcome in bladder cancer: Establishment of a predictive profile in a Southern Europe population . BJU I \n2015 ;116 :753 –63 .\n[35] \n\nChappidi \nMR \n, \nKates \nM \n, \nStimson \nCJ \n, \nJohnson \nMH \n, \nPierorazio \nPM \n, \nBivalacqua \nTJ \n. Causes, Timing, Hospital Costs, and Perioperative Outcomes Of Index vs. Non-Index Hospital Readmissions Following Radical Cystectomy: Implications For Regionalization of Care . J Urol \n2016 ;197 :296 –301 .27545575 \n[36] \n\nBotteman \nMF \n, \nPashos \nCL \n, \nRedaelli \nA \n, \nLaskin \nB \n, \nHauser \nR \n. The health economics of bladder cancer: A comprehensive review of the published literature . Pharmacoeconomics \n2003 ;21 :1315 –30 .14750899\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": null,
"issue": "3(4)",
"journal": "Bladder cancer (Amsterdam, Netherlands)",
"keywords": "Urinary bladder neoplasms; bladder; docetaxel; gemcitabine",
"medline_ta": "Bladder Cancer",
"mesh_terms": null,
"nlm_unique_id": "101668567",
"other_id": null,
"pages": "293-303",
"pmc": null,
"pmid": "29152553",
"pubdate": "2017-10-27",
"publication_types": "D016428:Journal Article",
"references": "10737480;14750899;16225511;16474654;16806414;17826484;17993339;18367121;20019985;20162706;20227172;21163569;21711438;22045349;23123371;23597452;23711538;23973518;24284001;24332121;24931268;25065995;25065996;25245244;25851338;26807434;26811532;26968418;27324428;27376138;27476032;27545575;27896277;28248951;28406148;30561441",
"title": "Oncological Outcomes of Sequential Intravesical Gemcitabine and Docetaxel in Patients with Non-Muscle Invasive Bladder Cancer.",
"title_normalized": "oncological outcomes of sequential intravesical gemcitabine and docetaxel in patients with non muscle invasive bladder cancer"
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"abstract": "Fluoroquinolones are widely prescribed antibiotics, used for various infectious etiologies. These antibiotics carry the possibility of the serious adverse effect of peripheral neuropathy, with a true incidence not known owing to its rare existence. Recently, the Food and Drug Administration (FDA) has required alterations to drug labels to highlight this adverse effect of fluoroquinolones. This is a case report of a single patient at an inpatient neurology service at an urban academic medical center in the United States. The patient is a 20-year-old male, with well-controlled type 1 diabetes mellitus, presenting with a short duration of bilateral lower extremity pain following a 10-day course of levofloxacin for suspected epididymitis. The patient was initially diagnosed with complex regional pain syndrome and treated with a variety of pain medications, including lidocaine infusions, hydromorphone, methadone, and ketamine infusions. After review of the patient's history and limited response to medical management, the patient's condition was reclassified as an adverse effect from fluoroquinolone treatment. Pain of unknown etiology can be perplexing, both for the physician and the patient. Reporting of similar incidents attributed to medication adverse effects will increase the awareness of this type of neuropathy, avoid future cases of misdiagnosis, and enable early detection and treatment.",
"affiliations": null,
"authors": "Dukewich|Matthew|M|;Danesh|Arash|A|;Onyima|Chiemeka|C|;Gupta|Anita|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D064704:Levofloxacin",
"country": "England",
"delete": false,
"doi": "10.1080/15360288.2017.1301619",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1536-0288",
"issue": "31(2)",
"journal": "Journal of pain & palliative care pharmacotherapy",
"keywords": "Food and Drug Administration; black box warning; complex regional pain syndrome; fluoroquinolone; lower extremity pain; peripheral neuropathy",
"medline_ta": "J Pain Palliat Care Pharmacother",
"mesh_terms": "D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D006801:Humans; D064704:Levofloxacin; D008297:Male; D010148:Pain, Intractable; D010523:Peripheral Nervous System Diseases; D055815:Young Adult",
"nlm_unique_id": "101125608",
"other_id": null,
"pages": "144-147",
"pmc": null,
"pmid": "28358229",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intractable Acute Pain Related to Fluoroquinolone-Induced Peripheral Neuropathy.",
"title_normalized": "intractable acute pain related to fluoroquinolone induced peripheral neuropathy"
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{
"companynumb": "US-PFIZER INC-2017158296",
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"occurcountry": "US",
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{
"abstract": "BACKGROUND Cocaine abuse is a globally recognized problem with great socioeconomic and health impacts on society. We report a case of dissection of vertebral arteries and right renal artery after cocaine abuse that clinically presented as atypical headache and hypertension. CASE REPORT A 36-year-old male sought emergency care due to cervical pain after cocaine abuse. The pain was located to the right cervical side with irradiation to the homolateral temporal region. He had no previous comorbidities, except for cocaine abuse on a weekly basis. Angiotomography showed alterations compatible with recent arterial dissection of the right vertebral artery, confirmed on angioresonance. The patient received double anti-aggregation and antihypertensive drugs and was discharged. He was readmitted 5 days later due to hypertensive crisis and mild abdominal pain. Abdominal ultrasound with a Doppler of renal arteries showed signs right renal artery stenosis. Magnetic resonance angiography confirmed dissection of the same vessel. The patient underwent arteriography with stent implantation in the right renal artery. During outpatient follow-up, he progressed with gradual reduction of antihypertensive drugs. CONCLUSIONS There is only 1 case report correlating renal artery dissection with cocaine use and none with concomitant presentation of dissection in the vertebral and renal arterial beds. The scarcity of reports is a consequence of many problems. Therefore, young patients presenting with new-onset hypertension or abdominal pain and cocaine abuse history should raise suspicion for renal artery dissection.",
"affiliations": "Nephrology Division, Federal University of São Paulo, São Paulo, SP, Brazil.;Department of Neurology, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.;Department of Neurology, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.;Department of Neurology, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.;Department of Vascular and Interventional Radiology, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.;Nephrology Division, Federal University of São Paulo, São Paulo, SP, Brazil.",
"authors": "Padilha|Wallace Stwart C|WSC|;Annes|Marcelo|M|;Massant|Cristina G|CG|;Kaup|Alexandre O|AO|;Affonso|Breno B|BB|;Batista|Marcelo C|MC|",
"chemical_list": "D003042:Cocaine",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.921565",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32094319\n10.12659/AJCR.921565\n921565\nArticles\nCocaine-Induced Renal Artery Dissection as a Cause of Secondary Hypertension: A Rare Presentation\nPadilha Wallace Stwart C. ABCDEF1 Annes Marcelo BCD2 Massant Cristina G. BCD2 Kaup Alexandre O. BCD2 Affonso Breno B. BCD3 Batista Marcelo C. ABCDE124 \n1 Nephrology Division, Federal University of São Paulo, São Paulo, SP, Brazil\n\n2 Department of Neurology, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil\n\n3 Department of Vascular and Interventional Radiology, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil\n\n4 Nephrology Division, New England Medical Center – Tufts, Boston, MA, U.S.A.\nCorresponding Author: Wallace Stwart C. Padilha, e-mail: wallace.stwart@gmail.comAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n25 2 2020 \n21 e921565-1 e921565-5\n20 11 2019 26 12 2019 24 1 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 36-year-old\n\nFinal Diagnosis: Vertebral and right renal arteries dissection due to cocaine abuse\n\nSymptoms: Abdominal discomfort • headache\n\nMedication: —\n\nClinical Procedure: Renal artery angioplasty\n\nSpecialty: General and Internal Medicine\n\nObjective:\nRare disease\n\nBackground:\nCocaine abuse is a globally recognized problem with great socioeconomic and health impacts on society. We report a case of dissection of vertebral arteries and right renal artery after cocaine abuse that clinically presented as atypical headache and hypertension.\n\nCase Report:\nA 36-year-old male sought emergency care due to cervical pain after cocaine abuse. The pain was located to the right cervical side with irradiation to the homolateral temporal region. He had no previous comorbidities, except for cocaine abuse on a weekly basis. Angiotomography showed alterations compatible with recent arterial dissection of the right vertebral artery, confirmed on angioresonance. The patient received double anti-aggregation and antihypertensive drugs and was discharged. He was readmitted 5 days later due to hypertensive crisis and mild abdominal pain. Abdominal ultrasound with a Doppler of renal arteries showed signs right renal artery stenosis. Magnetic resonance angiography confirmed dissection of the same vessel. The patient underwent arteriography with stent implantation in the right renal artery. During outpatient follow-up, he progressed with gradual reduction of antihypertensive drugs.\n\nConclusions:\nThere is only 1 case report correlating renal artery dissection with cocaine use and none with concomitant presentation of dissection in the vertebral and renal arterial beds. The scarcity of reports is a consequence of many problems. Therefore, young patients presenting with new-onset hypertension or abdominal pain and cocaine abuse history should raise suspicion for renal artery dissection.\n\nMeSH Keywords:\nCocaineDissectionHypertension, Renovascular\n==== Body\nBackground\nCocaine abuse is a globally recognized problem with great socioeconomic and health impacts on society. Its sporadic or habitual use can lead to a broad spectrum of organic dysfunctions, with varying degrees of severity. In this article, we report a case of dissection of the vertebral arteries and right renal artery after cocaine abuse that clinically presented as atypical headache and a cause of secondary hypertension, followed by a brief literature review.\n\nCase Report\nA 36-year-old male sought emergency care with a complaint of pain in the cervical region for 7 days, refractory to the use of simple analgesics and muscle relaxant. He reported that pain was located to the right cervical side with irradiation to the homolateral temporal region, of high intensity, which worsens when lying down or rotating the neck, and improves when standing. At the entrance he was afebrile, heart rate of 80 beats per minute, eupneic and hypertensive (170/130 mmHg). At physical examination, the patient reported pain on palpation of the temporal region, with no other relevant changes. Regarding the antecedents, the patient denied previous hyper-tension, other diseases or medication of continuous use. He had a moderate amount of alcohol ingestion at social events, 1 to 2 times a month, and smoking habit of 8 pack-year. When actively questioned, he reported being a cocaine user, on a weekly basis, and that he had used it the night preceding the onset of symptoms.\n\nAn evaluation of the on-call neurologist was requested, which, considering the atypical and new onset headache, indicated a cranial and cervical angiotomography. In the tomography, irregularities were found along with the cervical segments of the vertebral arteries, more extensive to the right side where there were signs of subocclusion, and the findings were compatible with recent arterial dissection (Figure 1). Subsequently, the diagnosis was confirmed by magnetic resonance angiography of cervical and cranial vessels, performed on the same date (Figure 2). Transcranial doppler ultrasound did not reveal any significant change in brain posterior circulation.\n\nThe patient was treated with double anti-aggregation with aspirin 100 mg daily and clopidogrel 75 mg daily, plus losartan 50 mg twice a day and amlodipine 5 mg daily to control blood pressure, being discharged after 2 days for outpatient follow-up. However, 5 days after discharge, the patient returned due to a hypertensive crisis, being hospitalized for further evaluation. At the time of readmission, the patient’s blood pressure was 160/100 mmHg, having denied cocaine use during the period in which he was at home. He also reported mild abdominal pain of low intensity, with no associated symptoms, and no relevant findings on physical examination. Due to the complaint of abdominal pain, an abdominal ultrasound with a Doppler of renal arteries was requested and showed normal-sized kidneys, with velocities of acceleration and pulsatility of the intraparenchymal branches of the right renal artery reduced, indicating probable downstream stenosis.\n\nTo complement the investigation, the patient underwent magnetic angio-resonance of renal arteries, which showed the presence of right renal artery dissection (Figure 3). The impact of dissection on renal function was measured by renal scintigraphy with DMSA (dimercapto succinic acid), showing a reduction of the glomerular and tubular function of the right kidney, according to Figure 4. Additionally, the patient underwent continuous blood pressure monitoring for 24 hours, confirming high blood pressure levels, with an average of 152/112 mmHg.\n\nDue to the high blood pressure levels despite antihypertensive treatment intensification and the risk of progression of the arterial dissection in the renal bed, we decided to initiate interventional treatment. The patient underwent arteriography by percutaneous approach of the right femoral artery, with self-expanding stent implantation in the right renal artery (Figures 5, 6). The arteriographic control showed improvement of the renal arterial flow and venous return (Figure 7).\n\nHe was submitted to a Doppler ultrasonography of renal arteries that demonstrated adequate flow of the right renal artery, with normalization of the spectral pattern and the relationship between the systolic velocities of the aorta and renal arteries, along with the patent stent in the right renal artery. He was discharged on the fifth day of hospitalization, asymptomatic, with a blood pressure of 130×80 mmHg and no changes on physical examination.\n\nAt the time of discharge, he was on losartan 50 mg twice daily, amlodipine 5 mg daily, nebivolol 5 mg daily, aspirin 100 mg daily and clopidogrel 75 mg daily. During outpatient follow-up, he progressed with gradual reduction of antihypertensive drugs.\n\nDiscussion\nTo our knowledge, there is only 1 case report published correlating renal artery dissection to cocaine use [1], and no case reports with concomitant dissection of the vertebral and renal arterial beds. Most likely, the scarcity of reports is a consequence of multiple factors, among these factors are the difficulty in diagnosis due to the often non-specific clinical presentation, the difficult causal correlation with cocaine abuse, and the lack of consideration of this diagnostic hypothesis by the physician, being therefore an under reported entity.\n\nCocaine is extracted from the leaves of the Erythroxylum coca plant and is now the second most widely consumed drug in the United States of America and Europe, supplanted only by marijuana use. In the United States, in the years 2016 and 2017, 14.4% and 14.9% of the population over 12 years of age, respectively, reported having ever used cocaine throughout their lives [2]. It acts stimulating the sympathetic nervous system, inhibiting the reuptake of noradrenaline and dopamine from the presynaptic slit and increasing its supply at postsynaptic receptors [3]. In addition, as it also blocks sodium and potassium channels, it behaves similarly to class I anti-arrhythmic agents and to local anesthetics [4].\n\nGiven its sympathomimetic effects, the initial signs and symptoms result from the stimulation of alpha-1, beta-adrenergic receptors, and cardiomyocytes, which clinically translates into increased heart rate, palpitation, increased blood pressure and myocardial contractility. The latter leads to increased myocardial oxygen consumption, which associated with coronary artery vasoconstriction may result in myocardial ischemia, a more prominent effect in patients with previous coronary artery disease [5].\n\nIn the vasculature system, multiple mechanisms participate in tissue ischemia due to the use of cocaine. The most likely is vasospasm due to the increased demand for oxygen in tissues and vessels. However, the formation of arterial thrombi by the activation and aggregation of platelets induced by the consumption of cocaine also participates; the mechanisms involve the increase of the plasma concentration of von Willebrand factor, greater shear stress in the endothelial wall, as well as increase of tissue factor expression by the endothelium [3].\n\nIn relation to the dissection of several arterial vascular beds already described, its genesis is multifactorial. Acceleration of the atherosclerotic process of the vessels in cocaine users has been reported, which favors the fragility of the arterial aspect [6]. At the molecular level, cocaine induces apoptosis of the smooth muscle cells of the arterial wall, a phenomenon that occurs in a concentration-dependent manner [7]. Signaling for apoptosis may be the result of increased production of reactive oxygen species-mediated by the drug, which leads to mitochondrial dysfunction and consequent induction of apoptosis [8].\n\nEdmondson et al. [1] described the only case of renal artery dissection published so far in a 40-year-old male cocaine user who presented to the emergency department with severe abdominal pain associated with low back pain occurring 2 months after cocaine abuse had ceased. Dissection of the right renal artery was confirmed by imaging, associated with multiple areas of renal infarction. The therapy consisted of open vascular surgery associated with anticoagulation with warfarin.\n\nConsistent with our report, both are young male patients, evolving with right renal artery dissection, but with different clinical presentations. In our case, the symptomatology was mild, and the main finding was secondary hypertension. In the external case, the clinical presentation was more exuberant, with no report of hypertension and with a greater time gap between last drug consumption and first symptoms, indicating that vascular wall fragility persists for some time even after cessation of cocaine use.\n\nConclusions\nTherefore, whenever a young patient with a history of cocaine abuse reports to a medical center or clinic with abdominal pain or recent onset of hypertension, the on-call physician should raise suspicion for renal artery dissection and further evaluation with image examination must be considered.\n\nFigure 1. Computed tomography angiography of the neck and brain. Irregularities along with the cervical segments of the vertebral arteries (red arrows), more extensive to the right side where there are signs of subocclusion. The findings are consistent with recent arterial dissection.\n\nFigure 2. Magnetic resonance angiography of the neck and brain. Signs of recent arterial dissection in the V1/V2 segment of the right vertebral artery (right red arrow), determining a moderate reduction of its lumen. Discrete irregularities in the contours of the V1/V2 and proximal V2 transition in the left vertebral artery (left red arrow), with a small image in addition in its mesial contour (red asterisk), without clear intramural hematoma, determining discrete luminal reductions, and may be related to the sequelae of previous dissection.\n\nFigure 3. Magnetic resonance angiography of the renal arteries. Single and patent right renal artery, with flap of focal dissection in the proximal third, about 1.5 cm from the emergency, and deficit of contrasting the middle and distal segments (red arrow).\n\nFigure 4. Renal scintigraphy with 99mTc-DMSA. Preserved global renal tubular function. Right kidney (R) with moderate tubular function deficit. Absence of cortical scars. Left kidney (L) with preserved tubular function and no evidence of cortical scarring.\n\nFigure 5. Angiography and stent implantation in the right renal artery. Persistent right renal artery, with signs of extensive dissection in its trunk to the bifurcation of the segmental arteries (red arrow).\n\nFigure 6. Angiography and stent implantation in the right renal artery. Transposition of the dissection zone was performed, finding the true light followed by self-expanding stent implantation to treat dissection (red arrow).\n\nFigure 7. Angiography and stent implantation in the right renal artery. The arteriographic control revealed adequate stent placement as well as renal trunk recanalization (red arrow).\n==== Refs\nReferences:\n1. Edmondson DA Towne JB Foley DW Cocaine-induced renal artery dissection and thrombosis leading to renal infarction WMJ 2004 103 7 66 69 \n2. Substance Abuse and Mental Health Services Administration 2017 National Survey on Drug Use and Health:detailed tables USDHHS 2018 Available from: http://www.samhsa.gov/data/report/2017-nsduh-detailed-tables \n3. Talarico GP Crosta ML Giannico MB Cocaine and coronary artery diseases: A systematic review of the literature J Cardiovasc Med (Hagerstown) 2017 18 5 291 94 28306693 \n4. Schwartz BG Rezkalla S Kloner RA Cardiovascular effects of cocaine Circulation 2010 122 24 2558 69 21156654 \n5. Stankowski RV Kloner RA Rezkalla SH Cardiovascular consequences of cocaine use Trends Cardiovasc Med 2015 25 6 517 26 25657055 \n6. Bachi K Mani V Jeyachandran D Vascular disease in cocaine addiction Atherosclerosis 2017 262 154 62 28363516 \n7. Su J Li J Li W Cocaine induces apoptosis in primary cultured rat aortic vascular smooth muscle cells: Possible relationship to aortic dissection, atherosclerosis, and hypertension Int J Toxicol 2004 23 4 233 37 15371167 \n8. Graziani M Sarti P Arese M Cardiovascular mitochondrial dysfunction induced by cocaine: biomarkers and possible beneficial effects of modulators of oxidative stress Oxid Med Cell Longev 2017 2017 3034245 28593024\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D000784:Aneurysm, Dissecting; D003042:Cocaine; D000072226:Computed Tomography Angiography; D006801:Humans; D006978:Hypertension, Renovascular; D018810:Magnetic Resonance Angiography; D008297:Male; D012077:Renal Artery; D000069322:Self Expandable Metallic Stents; D020217:Vertebral Artery Dissection",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e921565",
"pmc": null,
"pmid": "32094319",
"pubdate": "2020-02-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28593024;21156654;15371167;28306693;15696837;25657055;28363516",
"title": "Cocaine-Induced Renal Artery Dissection as a Cause of Secondary Hypertension: A Rare Presentation.",
"title_normalized": "cocaine induced renal artery dissection as a cause of secondary hypertension a rare presentation"
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"companynumb": "BR-GENUS_LIFESCIENCES-USA-POI0580202000220",
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"activesubstancename": "COCAINE HYDROCHLORIDE"
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{
"abstract": "Although neutropenia is a common complication after lung transplant, its relationship with recipient outcomes remains understudied. We evaluated a retrospective cohort of 228 adult lung transplant recipients between 2008 and 2013 to assess the association of neutropenia and granulocyte colony-stimulating factor (GCSF) treatment with outcomes. Neutropenia was categorized as mild (absolute neutrophil count 1000-1499), moderate (500-999), or severe (<500) and as a time-varying continuous variable. Associations with survival, acute rejection, and chronic lung allograft dysfunction (CLAD) were assessed with the use of Cox proportional hazards regression. GCSF therapy impact on survival, CLAD, and acute rejection development was analyzed by propensity score matching. Of 228 patients, 101 (42.1%) developed neutropenia. Recipients with severe neutropenia had higher mortality rates than those of recipients with no (adjusted hazard ratio [aHR] 2.97, 95% confidence interval [CI] 1.05-8.41, P = .040), mild (aHR 14.508, 95% CI 1.58-13.34, P = .018), or moderate (aHR 3.27, 95% CI 0.89-12.01, P = .074) neutropenia. Surprisingly, GCSF treatment was associated with a higher risk for CLAD in mildly neutropenic patients (aHR 3.49, 95% CI 0.93-13.04, P = .063), although it did decrease death risk in severely neutropenic patients (aHR 0.24, 95% CI 0.07-0.88, P = .031). Taken together, our data point to an important relationship between neutropenia severity and GCSF treatment in lung transplant outcomes.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, Missouri.;Division of Cardiothoracic Surgery, Department of Surgery, Washington University, St. Louis, Missouri.;Division of Biostatistics, Washington University, St. Louis, Missouri.;Division of General Medical Sciences, Washington University, St. Louis, Missouri.;Department of Surgery and Carter Center for Immunology, University of Virginia, Charlottesville, Virginia.;Division of Cardiothoracic Surgery, Department of Surgery, Washington University, St. Louis, Missouri.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, Missouri.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, Missouri.;Division of Cardiothoracic Surgery, Department of Surgery, Washington University, St. Louis, Missouri.",
"authors": "Tague|Laneshia Karee|LK|0000-0002-6243-1901;Scozzi|Davide|D|;Wallendorf|Michael|M|;Gage|Brian F|BF|;Krupnick|Alexander S|AS|0000-0002-1790-6197;Kreisel|Daniel|D|0000-0002-7711-8651;Byers|Derek|D|;Hachem|Ramsey R|RR|;Gelman|Andrew E|AE|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15581",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "20(1)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical decision-making; clinical research/practice; complication: infectious; innate immunity; lung transplantation/pulmonology; patient survival; rejection",
"medline_ta": "Am J Transplant",
"mesh_terms": "D064591:Allografts; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008171:Lung Diseases; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D015996:Survival Rate; D066027:Transplant Recipients",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "250-261",
"pmc": null,
"pmid": "31452317",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "21157041;26336061;25994524;28178208;15244498;19497072;28299345;11897517;10946260;30230362;24890728;27707998;27772669;16980323;10573067;24182778;25359357;30992538;16574228;29781563;29357983;18096473;23746202;23514290;30174163;28314052;30171223;19696633;21205990;21190834;16251851;25410813;30962148;23953556;23018463;21972291;19191800;18455007;19538494;27776691;21512429;27344051",
"title": "Lung transplant outcomes are influenced by severity of neutropenia and granulocyte colony-stimulating factor treatment.",
"title_normalized": "lung transplant outcomes are influenced by severity of neutropenia and granulocyte colony stimulating factor treatment"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP002573",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditiona... |
{
"abstract": "The aim of this study is to evaluate the pathological findings of the eye after intravitreal melphalan for viable vitreous seeding from retinoblastoma. All enucleated eyes receiving an intravitreal injection of melphalan (10-50 μg in 0.05 cc) were evaluated for histological changes. Of 25 treated cases, 8 eyes needed enucleation because of phthisis, parent request, or new tumor development. One of the cases was excluded from the study because of a history of intra-arterial chemotherapy with melphalan. There was no case of needle-site scleral involvement by retinoblastoma cells. In two eyes receiving 50 μg melphalan, no viable retinoblastoma cell was detectable in the eye. Severe gliosis, vascular occlusion, retinal necrosis, hemorrhage and neovascularization were seen. Histologically, intravitreal melphalan for recalcitrant or recurrent vitreous seeds from retinoblastoma appears to provide acceptable vitreous seed control. It seems that higher doses could be destructive causing ischemic necrosis in the retina, severe gliosis and secondary neovascular changes as well as having a destructive effect on retinoblastoma cells.",
"affiliations": "Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Qazvin Square, South Kargar, 1336616351, Tehran, Islamic Republic of Iran, fariba.ghassemi@gmail.com.",
"authors": "Ghassemi|Fariba|F|;Amoli|Fahimeh Asadi|FA|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10792-013-9851-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5701",
"issue": "34(3)",
"journal": "International ophthalmology",
"keywords": null,
"medline_ta": "Int Ophthalmol",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D002675:Child, Preschool; D015353:Eye Enucleation; D006801:Humans; D007223:Infant; D058449:Intravitreal Injections; D008558:Melphalan; D009366:Neoplasm Seeding; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D012189:Retrospective Studies; D014822:Vitreous Body",
"nlm_unique_id": "7904294",
"other_id": null,
"pages": "533-40",
"pmc": null,
"pmid": "24043335",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": "22694968;21746972;22801832;21273941;12912690;10696744;8437830;21670328;21149791;8533651;13890561;3115934;16996605;20693555;23044940;21813093;22174572;7295123;21399766;9682701;18342944;4966433;22427570",
"title": "Pathological findings in enucleated eyes after intravitreal melphalan injection.",
"title_normalized": "pathological findings in enucleated eyes after intravitreal melphalan injection"
} | [
{
"companynumb": "IR-GLAXOSMITHKLINE-B1020760A",
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"activesubstance": {
"activesubstancename": "MELPHALAN"
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... |
{
"abstract": "We would like to present the case of eruptive keratoacanthomas associated with dupilumab therapy, which occurred in an 85-year-old woman receiving biologic therapy for the treatment of atopic dermatitis. With the increasing prevalence of Dupilumab usage, this is an important potential complication of which clinicians should be aware.",
"affiliations": "East Surrey Hospital, Surrey and Sussex Healthcare NHS Trust, Redhill, UK.;East Surrey Hospital, Surrey and Sussex Healthcare NHS Trust, Redhill, UK.;East Surrey Hospital, Surrey and Sussex Healthcare NHS Trust, Redhill, UK.",
"authors": "Gleeson|D|D|https://orcid.org/0000-0002-7355-9281;Cliff|S|S|;Das|M|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bjd.20781",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0963",
"issue": null,
"journal": "The British journal of dermatology",
"keywords": null,
"medline_ta": "Br J Dermatol",
"mesh_terms": null,
"nlm_unique_id": "0004041",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34608625",
"pubdate": "2021-10-05",
"publication_types": "D016422:Letter",
"references": null,
"title": "Eruptive keratoacanthomas associated with dupilumab therapy.",
"title_normalized": "eruptive keratoacanthomas associated with dupilumab therapy"
} | [
{
"companynumb": "GB-NOVARTISPH-NVSC2022GB023611",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
... |
{
"abstract": "3- and 4-methoxyphencyclidine (3-MeO-PCP, 4-MeO-PCP), structural analogs of phencyclidine (PCP), were among the first legal PCP alternatives to show up on the novel psychoactive substances (NPS) market in Europe in the 2000s. Their structural similarities to PCP and ketamine likely contribute to their demonstrated dissociative anesthetic effects. Limited information exists in the literature about toxic and lethal concentrations of these drugs in biological samples. This case report presents the first two death cases in Washington State in which 3-MeO-PCP was identified. Alkaline drug screen analysis by gas chromatography-mass spectrometry (GC-MS) revealed a peak with a retention time similar to PCP and base peak of m/z 230. Certified reference materials for 3-and 4-MeO-PCP were obtained and the isomers were able to be distinguished based on different retention times and mass spectra. A quantitative GC-MS method was developed and validated for casework, utilizing a dynamic range of 10-1,000 ng/mL and a limit of detection of 1 ng/mL. Postmortem (peripheral/central) blood samples were analyzed using this method and the resulting concentrations were 0.63 and 3.2 mg/L of 3-MeO-PCP. Methamphetamine (0.11 mg/L) was additionally detected in the blood of one of the decedents; while the second decedent was additionally positive for ethanol (0.047 g/100 mL), bupropion (1.8 mg/L), delorazepam, paroxetine and mitragynine. The results presented in this case report are higher than previously reported concentrations in fatal cases, but the presence of polysubstance abuse is consistent with previously reported NPS intoxications. Both of these individuals were in drug rehabilitation facilities prior to their deaths; however, users continue to be drawn to 3-MeO-PCP due to its dissociative effects and its accessibility on the internet.",
"affiliations": "Email: Christie.Mitchell@wsp.wa.gov;Washington State Toxicology Laboratory, 2203 Airport Way S Suite 360, Seattle, WA 98134, USA.;Washington State Toxicology Laboratory, 2203 Airport Way S Suite 360, Seattle, WA 98134, USA.;Washington State Toxicology Laboratory, 2203 Airport Way S Suite 360, Seattle, WA 98134, USA.",
"authors": "Mitchell-Mata|Christie|C|;Thomas|Brittany|B|;Peterson|Brianna|B|;Couper|Fiona|F|",
"chemical_list": "D013287:Illicit Drugs; D011619:Psychotropic Drugs; C578785:methoxydine; D010622:Phencyclidine",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkx048",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "41(6)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D062787:Drug Overdose; D006801:Humans; D013287:Illicit Drugs; D010622:Phencyclidine; D011619:Psychotropic Drugs; D015813:Substance Abuse Detection; D014861:Washington",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "503-507",
"pmc": null,
"pmid": "28830118",
"pubdate": "2017-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two Fatal Intoxications Involving 3-Methoxyphencyclidine.",
"title_normalized": "two fatal intoxications involving 3 methoxyphencyclidine"
} | [
{
"companynumb": "PHHY2017US197643",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PAROXETINE"
},
"drugadditional": null,
"drug... |
{
"abstract": "In this study, a case is presented in which initiation of an antidepressant drug was associated with an episode of extreme sedation. This case provides an opportunity to highlight possible pitfalls in geriatric prescribing.",
"affiliations": "Tokachi- Ikeda Community Medical Center, Japan Association for Development of Community Medicine, Ikeda, 0830022 Hokkaido, Japan.",
"authors": "Namiki|Hirofumi|H|0000-0002-9917-0493",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2019/4290207",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2019/4290207Case ReportPitfalls in Geriatric Prescribing: Antidepressants and Extreme Sedation http://orcid.org/0000-0002-9917-0493Namiki Hirofumi hirofumin@jadecom.jpTokachi- Ikeda Community Medical Center, Japan Association for Development of Community Medicine, Ikeda, 0830022 Hokkaido, JapanAcademic Editor: Georgios D. Kotzalidis\n\n2019 13 5 2019 2019 429020726 2 2019 5 5 2019 Copyright © 2019 Hirofumi Namiki.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.In this study, a case is presented in which initiation of an antidepressant drug was associated with an episode of extreme sedation. This case provides an opportunity to highlight possible pitfalls in geriatric prescribing.\n==== Body\n1. Introduction\nCoupland et al. [1] have previously reported the risk of adverse effects secondary to the use of antidepressants in the elderly. Antidepressants are commonly prescribed for a range of therapeutic indications, such as treatment of depression and management of neuropathic pain [2]. These uses are associated with several well-recognized adverse effects, including sexual dysfunction, weight change, bleeding, cardiovascular effects, and anticholinergic effects [3]. However, another significant adverse effect of antidepressant drugs is extreme sedation.\n\n2. Case Presentation\nA 92-year-old man was admitted to hospital with a general decline in functional status. A comprehensive geriatric assessment revealed low mood without evidence of cognitive impairment, and a diagnosis of depression was made. The patient was prescribed mirtazapine 7.5 mg nocte per oral, and the following day, he became increasingly unstable. Two days later, the patient was found unresponsive in bed.\n\nThere was no history of head trauma, and no seizure activity was observed. Vital signs were unremarkable, while respiratory, cardiovascular, and abdominal examinations were normal. However, neurological examination revealed diminished mental status. The patient did respond to a deep, painful stimulus but his eyes remained closed, and there was no verbal response. The patient had brisk deep tendon reflexes and showed plantar reflexes of the extensor. Blood tests (including those for urea, electrolytes, glucose, calcium, magnesium, Vitamin B12 and folate levels, C-reactive protein, thyroid function, and full blood count) were normal. An electrocardiogram displayed normal sinus rhythm, and an emergency magnetic resonance brain scan demonstrated no evidence of acute intracranial pathology.\n\nThe patient's level of consciousness gradually returned to normal after 4 hours. The antidepressant-induced sedation was suspected of being the cause, and mirtazapine was immediately stopped. There was no subjective improvement in mood after withdrawal of mirtazapine. Three days later, the patient was re-prescribed on mirtazapine 3.75 mg nocte. Though he appeared expressionless, he gradually became more responsive after a week. Following the reduction of mirtazapine dose, the patient did not experience any more episodes of extreme sedation during a 2-month follow-up.\n\n3. Discussion\nThis case is a teaching example of antidepressant-induced extreme sedation in a geriatric prescription for depression. Depression is the most common mental health disorder with life-threatening consequences and affects up to 13.3% of the elderly population [4]. Beekman et al. [5] reported that disability is an essential determinant in the prevalence of depression in the elderly, with inpatients with long-term conditions and those living in adverse socioeconomic circumstances having a higher prevalence than people living in the community and those of average socioeconomic status. In this case, following the withdrawal of the antidepressant, a smaller dose of antidepressant was reintroduced to avoid extreme sedation. The patient experienced an additional, yet reduced sedative episode following a smaller dose of antidepressant. This episode could conclusively prove that the antidepressant had produced the extreme sedation. The sedative effect of antidepressants has been rarely discussed. This case provides an opportunity to highlight the importance of depression in this population, as well as potential behavioral mechanisms associated with antidepressants, and more generally, appropriate prescribing in the elderly.\n\nAccording to the NHS Grampian Guidance for Initiating Antidepressants, which was developed according to guidance by the National Institute for Health and Care Excellence, mirtazapine and sertraline are both first-line treatments for depression in older people [6, 7]. Mirtazapine is classified as atypical antidepressant and described as a noradrenergic and specific serotonergic antidepressant (NaSSA). Mirtazapine is specifically a potent antagonist or inverse agonist of the alpha2-adrenergic receptor, the serotonin 5-HT2 receptor, 5-HT3 receptor, H1 histamine receptor, a moderate peripheral alpha-adrenergic receptor, and muscarinic receptor antagonist. Moreover, antimuscarinic action in mirtazapine could lead to sedation during initial treatment. Indeed, mirtazapine is usually given at night due to its sedating effect [8, 9].\n\nSertraline is another antidepressant that can also cause drowsiness [10]. On acute use, sertraline can selectively block serotonin reuptake and can increase serotonin stimulation of somatodendritic 5HT1 but has only weak effects on norepinephrine and neuronal dopamine uptake [11]. However, there is evidence that sertraline has a benefit over other classes of antidepressants in terms of safety or tolerability for the acute phase of severe depression treatment [12].\n\nPrescribing for older patients presents unique challenges because the elderly are often more sensitive to drugs and therefore are at increased risk of experiencing adverse effects. This is due to the pharmacokinetic and pharmacodynamic changes that occur with aging, including increased body fat composition, decreased lean mass, decreased P450 enzyme system activity, decreased renal excretion of drugs, and increased sensitivity to the effects of drugs. These factors are especially important when the drug involved has a narrow therapeutic range, which is the case with antidepressants [8, 13].\n\nFurthermore, adverse drug reactions commonly lead to hospital admission in the elderly [14–16]. According to Beijer and de Blaey [17], adverse drug reactions result in four times as many hospitalizations in older adults than in younger adults. The possibility of an adverse drug event should always be considered by clinicians when evaluating an older adult. In general, prescribing in the elderly should follow the pattern of “start low, go slow” to reduce the possibility of an adverse drug event. Moreover, polypharmacy is often observed in older people due to the presence of multiple comorbidities [8, 13]. Therefore, it is crucial that drugs be regularly reviewed and adverse drug effects actively considered, such that medications that do not provide significant clinical benefit are discontinued.\n\nPrescription of potentially inappropriate and excessive medications in older people is common. A review article by Gallagher et al. [18] reported that inappropriate and excessive medications are often prescribed, ranging from 12% of community-dwelling older people to 40% of nursing home residents in the USA and Europe. Given this high prevalence, the review recommends the use of pharmacogenetic decision support tools, which consider evidence-based prescription in the context of the clinician's practice, with consideration of diverse patient needs within each country's national formulary [19].\n\nAdditional discussion would be needed in elderly patients as follows. Many patients with depression who do not respond adequately to standard treatment with pharmacotherapy and psychotherapy are candidates for noninvasive neuromodulation procedures, including transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT) [20, 21]. Patients, especially the elderly, may prefer TMS because it is better tolerated; TMS does not require general anesthesia and induction of seizures. TMS, including deep TMS approved by the FDA, is a noninvasive, clinically available treatment with demonstrated efficacy [22].\n\nDespite the effectiveness of pharmacological treatments in depression, symptom remission has been achieved in fewer than 40% of elderly patients of depression with cognitive impairment, with or without dementia [23]. Therefore, effective psychosocial interventions for this patient population are needed. Most of the psychosocial interventions for geriatric depression are designed for young-old (average age, 65 to 70 years) and cognitively intact outpatients who could follow adequate treatment plans [24]. To effectively treat depressed elderly patients with comorbid cognitive impairment and disability, psychosocial interventions need to be comprehensively modified. With these modifications, psychosocial interventions could provide relief to many groups of elderly patients and synchronize to the elderly people's abilities, preferences, and needs aiming to prevent the onset of depression.\n\nConflicts of Interest\nThe author declares that there are no conflicts of interest regarding the publication of this paper.\n==== Refs\n1 Coupland C. Dhiman P. Morriss R. Arthur A. Barton G. Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in older people: population based cohort study BMJ 2011 343 2 p. d4551 10.1136/bmj.d4551 2-s2.0-80052913150 \n2 Mottram P. G. Wilson K. Strobl J. Antidepressants for depressed elderly Cochrane Database of Systematic Reviews 2006 1 CD003491 10.1002/14651858.CD003491.pub2 \n3 Olfson M. Marcus S. C. National patterns in antidepressant medication treatment Archives of General Psychiatry 2009 66 8 848 856 10.1001/archgenpsychiatry.2009.81 2-s2.0-68149148593 19652124 \n4 Baldwin R. Wild R. Management of depression in later life Advances in Psychiatric Treatment 2004 10 2 131 139 10.1192/apt.10.2.131 2-s2.0-1542711349 \n5 Beekman A. T. F. Copeland J. Prince M. J. Review of community prevalence of depression in later life British Journal of Psychiatry 1999 174 4 307 311 10.1192/bjp.174.4.307 10533549 \n6 NHS Grampian NHS Grampian Guidance for Initiating Antidepressants 2017 Aberdeen, Scotland NHS Grampian \n7 National Institute for Health and Clinical Excellence Depression in Adults. CG90 2009 London, UK National Institute for Health and Clinical Excellence \n8 BMJ Publishing Group British medical association and the royal pharmaceutical society of great britain British National Formulary 2018 76th London, UK BMJ Publishing Group \n9 Croom K. F. Perry C. M. Plosker G. L. Mirtazapine CNS Drugs 2009 23 5 427 452 10.2165/00023210-200923050-00006 2-s2.0-66249146404 19453203 \n10 Alderman J. Wolkow R. Chung M. Johnston H. F. Sertraline treatment of children and adolescents with obsessive-compulsive disorder or depression: pharmacokinetics, tolerability, and efficacy Journal of the American Academy of Child & Adolescent Psychiatry 1998 37 4 386 394 10.1097/00004583-199804000-00016 2-s2.0-0031967526 9549959 \n11 Ambrosini P. J. Wagner K. D. Biederman J. Multicenter open-label sertraline study in adolescent outpatients with major depression Journal of the American Academy of Child & Adolescent Psychiatry 1999 38 5 566 572 10.1097/00004583-199905000-00018 2-s2.0-13044300889 10230188 \n12 Cipriani A. La Ferla T. Furukawa T. A. Sertraline versus other antidepressive agents for depression Cochrane Database of Systematic Reviews 2009 2 CD006117 10.1002/14651858.CD006117 2-s2.0-84921623990 \n13 Routledge P. A. O’Mahony M. S. Woodhouse K. W. Adverse drug reactions in elderly patients British Journal of Clinical Pharmacology 2004 57 2 121 126 10.1046/j.1365-2125.2003.01875.x 2-s2.0-1242306685 14748810 \n14 Lazarou J. Pomeranz B. H. Corey P. N. Incidence of adverse drug reactions in hospitalized patients JAMA 1998 279 15 1200 1205 10.1001/jama.279.15.1200 2-s2.0-0032522873 9555760 \n15 Onder G. Pedone C. Landi F. Adverse drug reactions as cause of hospital admissions: results from the Italian Group of Pharmacoepidemiology in the Elderly (GIFA) Journal of the American Geriatrics Society 2002 50 12 1962 1968 10.1046/j.1532-5415.2002.50607.x 2-s2.0-0036904903 12473007 \n16 Pirmohamed M. James S. Meakin S. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients BMJ 2004 329 7456 15 19 10.1136/bmj.329.7456.15 15231615 \n17 Beijer H. J. M. de Blaey C. J. Hospitalisations caused by adverse drug reactions (ADR): a meta-analysis of observational studies Pharmacy World and Science 2002 24 2 46 54 12061133 \n18 Gallagher P. Barry P. O’Mahony D. Inappropriate prescribing in the elderly Journal of Clinical Pharmacy and Therapeutics 2007 32 2 113 121 10.1111/j.1365-2710.2007.00793.x 2-s2.0-33947384124 17381661 \n19 Bousman C. A. Forbes M. Jayaram M. Antidepressant prescribing in the precision medicine era: a prescriber’s primer on pharmacogenetic tools BMC Psychiatry 2017 17 1 p. 60 10.1186/s12888-017-1230-5 2-s2.0-85012048675 \n20 Rush A. J. Trivedi M. H. Wisniewski S. R. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR∗ D report American Journal of Psychiatry 2006 163 11 1905 1917 10.1176/ajp.2006.163.11.1905 2-s2.0-33751338530 17074942 \n21 Kennedy S. H. Milev R. Giacobbe P. Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines for the management of major depressive disorder in adults Journal of Affective Disorders 2009 117 1 S44 S53 10.1016/j.jad.2009.06.039 2-s2.0-69649083323 19656575 \n22 Bersani F. S. Girardi N. Sanna L. Deep transcranial magnetic stimulation for treatment-resistant bipolar depression: a case report of acute and maintenance efficacy Neurocase 2013 19 5 451 457 10.1080/13554794.2012.690429 2-s2.0-84885072583 22827578 \n23 Alexopoulos G. S. Depression in the elderly The Lancet 2005 365 9475 1961 1970 10.1016/S0140-6736(05)66665-2 2-s2.0-20444392780 \n24 Mackin R. S. Areán P. A. Evidence-based psychotherapeutic interventions for geriatric depression Psychiatric Clinics of North America 2005 28 4 805 820 10.1016/j.psc.2005.09.009 2-s2.0-28544442544 16325730\n\n",
"fulltext_license": "CC BY",
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"issue": "2019()",
"journal": "Case reports in medicine",
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"title": "Pitfalls in Geriatric Prescribing: Antidepressants and Extreme Sedation.",
"title_normalized": "pitfalls in geriatric prescribing antidepressants and extreme sedation"
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"abstract": "The number of long-acting injectable antipsychotics (LAIA) has increased in recent years. The safety and efficacy of that treatment are not established in children. This study aims to address this gap of information by studying such treatments in a case series.\n\n\n\nThis retrospective chart review of patients identified by the investigators at an academic acute inpatient psychiatric unit included all patients from the past 24 months who required new initial treatment with LAIA. This study included a case series of the nine patients along with Clinical Global Impression-Severity (CGI-S) scores from admission and discharge and Clinical Global Impression-Improvement (CGI-I) scores. Other observations included the presentation of primary psychiatric diagnosis, psychiatric and medical comorbidities, age, sex, previous and LAIA psychiatric medications, reasoning for LAIA treatment, adverse events, CGI-S and CGI-I scores, and outpatient resources utilized to continue treatment.\n\n\n\nThe case series included two females and seven males within the ages of 14-17 years. Of those patients, five were treated with paliperidone palmitate, one treated with risperidone, one treated with fluphenazine, and one treated with aripiprazole. Primary psychiatric diagnosis of the patients in the case series included five with schizophrenia, one with schizoaffective disorder, one with bipolar affective disorder-type I, one with bipolar affective disorder-not otherwise specified, and one with mood disorder-not otherwise specified. In all nine cases, noncompliance was a consideration in treatment with LAIA. Frequent running away and severity of illness were also considerations in one case each. All of the patients required community resources with injectable services.\n\n\n\nThis study describes initiation of treatment with LAIA in 14-17-year olds in an acute inpatient psychiatric unit with serious mental illness. This study also demonstrates the need for outpatient community resources with the ability to provide long-acting injectable medication. Limitations of this study include a small patient population, other factors changing CGI-S and CGI-I scores beyond the medication, and the nature of the study as a retrospective chart review. This study did not compare medications between each other. Maintenance dosing and long-term safety were beyond the scope of this study. Future directives for safety studies, open-label trials, and randomized double-blinded control trails in the pediatric population would be needed.",
"affiliations": "Division of Child & Adolescent Psychiatry, Department of Psychiatry, University Hospitals Case Medical Center , Cleveland, Ohio.;Division of Child & Adolescent Psychiatry, Department of Psychiatry, University Hospitals Case Medical Center , Cleveland, Ohio.",
"authors": "Pope|Stephanie|S|;Zaraa|Solomon G|SG|",
"chemical_list": "D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations",
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"delete": false,
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"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D005260:Female; D006760:Hospitalization; D006801:Humans; D007267:Injections; D007297:Inpatients; D008297:Male; D055118:Medication Adherence; D001523:Mental Disorders; D011569:Psychiatric Status Rating Scales; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "9105358",
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"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy of Long-Acting Injectable Antipsychotics in Adolescents.",
"title_normalized": "efficacy of long acting injectable antipsychotics in adolescents"
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"abstract": "The sodium voltage-gated channel α subunit 2 (SCN2A) gene encodes a subunit of sodium voltage-gated channels expressed primarily in the central nervous system that are responsible for action potential initiation and propagation in excitable cells. SCN2A mutations underlie a spectrum of distinct phenotypes, including seizure disorders, neurodevelopmental disorders, and rarer instances of episodic ataxia and schizophrenia. We report on a 38-year-old patient with adult-onset psychotic symptoms on a background of infantile-onset seizures, autistic features and episodic ataxia. Whole-exome sequencing revealed a de-novo novel SCN2A mutation (c.4966T > C, p.Ser1656Pro). This and other SCN2A mutations associated with the schizophrenia phenotype overlap those seen in neurodevelopmental disorders, suggesting a common underlying mechanism. This is the first report of a patient with the entire known SCN2A phenotypic spectrum. We highlight the importance of recognizing the psychiatric phenotypes associated with SCN2A mutations and that the phenotypic spectrum is more fluid, and less categorical, than previously thought.",
"affiliations": "The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital.;The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital.;The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital.",
"authors": "Suddaby|Jessica S|JS|;Silver|Josh|J|;So|Joyce|J|",
"chemical_list": "D062551:NAV1.2 Voltage-Gated Sodium Channel; C568251:SCN2A protein, human",
"country": "England",
"delete": false,
"doi": "10.1097/YPG.0000000000000219",
"fulltext": null,
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"issn_linking": "0955-8829",
"issue": "29(3)",
"journal": "Psychiatric genetics",
"keywords": null,
"medline_ta": "Psychiatr Genet",
"mesh_terms": "D000328:Adult; D001259:Ataxia; D004827:Epilepsy; D006801:Humans; D008297:Male; D009154:Mutation; D062551:NAV1.2 Voltage-Gated Sodium Channel; D065886:Neurodevelopmental Disorders; D010641:Phenotype; D012559:Schizophrenia; D012565:Schizophrenic Psychology; D000073359:Whole Exome Sequencing",
"nlm_unique_id": "9106748",
"other_id": null,
"pages": "91-94",
"pmc": null,
"pmid": "30741786",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Understanding the schizophrenia phenotype in the first patient with the full SCN2A phenotypic spectrum.",
"title_normalized": "understanding the schizophrenia phenotype in the first patient with the full scn2a phenotypic spectrum"
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"companynumb": "CA-MICRO LABS LIMITED-ML2020-01382",
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"abstract": "Significant concern exists over treating youths with attention-deficit/hyperactivity disorder (ADHD) with antipsychotic medications, yet little is known about the factors associated with antipsychotic treatment.\n\n\n\nTo describe the percentage of youths who fill antipsychotic prescriptions in the year following a new diagnosis of ADHD and characterize the clinical and demographic factors associated with antipsychotic initiation.\n\n\n\nA retrospective longitudinal cohort analysis of antipsychotic treatment was performed in 187 563 youths, aged 3 to 24 years, with a new diagnosis of ADHD (without recent diagnosis of any US Food and Drug Administration [FDA]-indicated conditions for antipsychotic treatment). The sample was derived from the 2010 to 2015 MarketScan Commercial Database, with the analysis completed between November 1, 2018, and May 30, 2019.\n\n\n\nThe percentage of youths prescribed an antipsychotic in the first year following a new diagnosis of ADHD. Among those prescribed antipsychotic medications, the percentage who received a diagnosis of conduct disorder, oppositional defiant disorder, or a disorder for which 1 or more antipsychotic medication has received an indication for use in youths from the FDA (schizophrenia, bipolar disorder, and Tourette disorder) and the percentage that filled an antipsychotic prescription before filling a stimulant prescription (methylphenidate or amphetamine derivative).\n\n\n\nOf the 187 563 youths included in the study, 114 305 (60.9%) were male with a mean (SD) age of 13.74 (5.61) years. In the year following a new ADHD diagnosis, 4869 youths (2.6%; 95% CI, 2.5%-2.7%) with ADHD were prescribed an antipsychotic. Youths treated with antipsychotics with ADHD were more likely than their peers who were not receiving an antipsychotic to have recently received diagnoses of self-harm and/or suicidal ideation (adjusted odds ratio [aOR], 7.5; 95% CI, 5.9-9.6), oppositional defiant disorder (aOR, 4.4; 95% CI, 3.9-4.9), and substance use disorder (aOR, 4.0; 95% CI, 3.6-4.5). The youths who received antipsychotics were also more likely to have received inpatient treatment (aOR, 7.9; 95% CI, 6.7-9.3). During the year following the new ADHD diagnosis, 52.7% (95% CI, 51.3%-54.1%) of youths treated with antipsychotics received a diagnosis for which antipsychotics have either an FDA or evidence-supported indication for their use. Among youths who initiated antipsychotic medications, 47.9% (95% CI, 46.5%-49.3%) did not receive a stimulant prescription between their ADHD diagnosis and antipsychotic initiation. Antipsychotic prescribing was proportionally highest for preschool-aged children (4.3%) and associated with neurodevelopmental disorders (aOR, 3.9; 95% CI, 1.3-11.2) and recent inpatient mental health treatment (aOR, 8.9; 95% CI, 1.7-45.8).\n\n\n\nApproximately half of youths with a new ADHD diagnosis may have an evidence-supported indication for an antipsychotic medication. Less than half of these youths received a stimulant; the evidence-supported first line treatment for ADHD, before the antipsychotic was initiated. Use of antipsychotic prescribing appears to be associated with high levels of psychiatric comorbidity.",
"affiliations": "Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.;Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.;Institute for Health, Health Care Policy, and Aging Research, Rutgers University, New Brunswick, New Jersey.;Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.",
"authors": "Sultan|Ryan S|RS|;Wang|Shuai|S|;Crystal|Stephen|S|;Olfson|Mark|M|",
"chemical_list": "D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants",
"country": "United States",
"delete": false,
"doi": "10.1001/jamanetworkopen.2019.7850",
"fulltext": "\n==== Front\nJAMA Netw OpenJAMA Netw OpenJAMA Netw OpenJAMA Network Open2574-3805American Medical Association 10.1001/jamanetworkopen.2019.7850zoi190313ResearchOriginal InvestigationOnline OnlyPsychiatryAntipsychotic Treatment Among Youths With Attention-Deficit/Hyperactivity Disorder Antipsychotic Treatment Among Youths With Attention-Deficit/Hyperactivity DisorderAntipsychotic Treatment Among Youths With Attention-Deficit/Hyperactivity DisorderSultan Ryan S. MD12Wang Shuai PhD12Crystal Stephen PhD3Olfson Mark MDMPH121 Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York2 New York State Psychiatric Institute, New York3 Institute for Health, Health Care Policy, and Aging Research, Rutgers University, New Brunswick, New JerseyArticle Information\nAccepted for Publication: June 6, 2019.\n\nPublished: July 26, 2019. doi:10.1001/jamanetworkopen.2019.7850\n\nOpen Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Sultan RS et al. JAMA Network Open.\n\nCorresponding Author: Ryan S. Sultan, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, 1051 Riverside Dr, PO Box 78, New York, NY 10032 (rs3511@cumc.columbia.edu).Author Contributions: Drs Sultan and Olfson had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.\n\nConcept and design: Sultan, Crystal, Olfson.\n\nAcquisition, analysis, or interpretation of data: Sultan, Wang, Crystal.\n\nDrafting of the manuscript: Sultan, Crystal, Olfson.\n\nCritical revision of the manuscript for important intellectual content: Sultan, Wang, Crystal, Olfson.\n\nStatistical analysis: Sultan, Wang, Crystal.\n\nObtained funding: Sultan, Crystal, Olfson.\n\nAdministrative, technical, or material support: Sultan.\n\nSupervision: Sultan, Olfson.\n\nConflict of Interest Disclosures: Dr Olfson reported receiving personal fees from Lundbeck Pharmaceuticals during the conduct of the study. No other disclosures were reported.\n\nFunding/Support: This study was supported by grants 1R01HS026001-01A1 and U19HS021112-01 from the Agency for Healthcare Research and Quality and the American Academy of Child and Adolescent Psychiatry Pilot Research Award for Attention Disorders.\n\nRole of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.\n\n26 7 2019 7 2019 26 7 2019 2 7 e19785022 3 2019 6 6 2019 Copyright 2019 Sultan RS et al. JAMA Network Open.This is an open access article distributed under the terms of the CC-BY License.jamanetwopen-2-e197850.pdfKey Points\nQuestion\nHow commonly are youths with attention-deficit/hyperactivity disorder treated with antipsychotic medications and what factors are associated with their use of antipsychotic treatment?\n\nFindings\nIn this cohort study of 187 563 commercially insured youths with new episodes of attention-deficit/hyperactivity disorder, 2.3% were treated with an antipsychotic medication, among whom 52.7% had a potential clinical diagnostic rationale for antipsychotic treatment. Factors for antipsychotic medication use included older patient age, male sex, recent inpatient and other pharmacologic mental health treatments, self-harm/suicidal ideation; and oppositional defiant, substance use, depressive, and anxiety disorders.\n\nMeaning\nApproximately 1 in 40 commercially insured youths were treated with an antipsychotic medication without an approved indication in the year following a new attention-deficit/hyperactivity disorder diagnosis; mental health comorbidities may be associated with antipsychotic treatment in this group.\n\nImportance\nSignificant concern exists over treating youths with attention-deficit/hyperactivity disorder (ADHD) with antipsychotic medications, yet little is known about the factors associated with antipsychotic treatment.\n\nObjectives\nTo describe the percentage of youths who fill antipsychotic prescriptions in the year following a new diagnosis of ADHD and characterize the clinical and demographic factors associated with antipsychotic initiation.\n\nDesign, Setting, and Participants\nA retrospective longitudinal cohort analysis of antipsychotic treatment was performed in 187 563 youths, aged 3 to 24 years, with a new diagnosis of ADHD (without recent diagnosis of any US Food and Drug Administration [FDA]–indicated conditions for antipsychotic treatment). The sample was derived from the 2010 to 2015 MarketScan Commercial Database, with the analysis completed between November 1, 2018, and May 30, 2019.\n\nMain Outcomes and Measures\nThe percentage of youths prescribed an antipsychotic in the first year following a new diagnosis of ADHD. Among those prescribed antipsychotic medications, the percentage who received a diagnosis of conduct disorder, oppositional defiant disorder, or a disorder for which 1 or more antipsychotic medication has received an indication for use in youths from the FDA (schizophrenia, bipolar disorder, and Tourette disorder) and the percentage that filled an antipsychotic prescription before filling a stimulant prescription (methylphenidate or amphetamine derivative).\n\nResults\nOf the 187 563 youths included in the study, 114 305 (60.9%) were male with a mean (SD) age of 13.74 (5.61) years. In the year following a new ADHD diagnosis, 4869 youths (2.6%; 95% CI, 2.5%-2.7%) with ADHD were prescribed an antipsychotic. Youths treated with antipsychotics with ADHD were more likely than their peers who were not receiving an antipsychotic to have recently received diagnoses of self-harm and/or suicidal ideation (adjusted odds ratio [aOR], 7.5; 95% CI, 5.9-9.6), oppositional defiant disorder (aOR, 4.4; 95% CI, 3.9-4.9), and substance use disorder (aOR, 4.0; 95% CI, 3.6-4.5). The youths who received antipsychotics were also more likely to have received inpatient treatment (aOR, 7.9; 95% CI, 6.7-9.3). During the year following the new ADHD diagnosis, 52.7% (95% CI, 51.3%-54.1%) of youths treated with antipsychotics received a diagnosis for which antipsychotics have either an FDA or evidence-supported indication for their use. Among youths who initiated antipsychotic medications, 47.9% (95% CI, 46.5%-49.3%) did not receive a stimulant prescription between their ADHD diagnosis and antipsychotic initiation. Antipsychotic prescribing was proportionally highest for preschool-aged children (4.3%) and associated with neurodevelopmental disorders (aOR, 3.9; 95% CI, 1.3-11.2) and recent inpatient mental health treatment (aOR, 8.9; 95% CI, 1.7-45.8).\n\nConclusions and Relevance\nApproximately half of youths with a new ADHD diagnosis may have an evidence-supported indication for an antipsychotic medication. Less than half of these youths received a stimulant; the evidence-supported first line treatment for ADHD, before the antipsychotic was initiated. Use of antipsychotic prescribing appears to be associated with high levels of psychiatric comorbidity.\n\nThis cohort study examines the use of antipsychotic medication in youths, aged 3 to 24 years, following a new diagnosis of attention-deficit/hyperactivity disorder.\n==== Body\nIntroduction\nIn the past decade, there has been an increase in the prescription of antipsychotic medications to children and adolescents.1,2,3,4 Between 1999 and 2014, antipsychotic prescribing for young people in the United States increased by 50%.4 Some of the increase in antipsychotic medication use in youths was for clinical indications that have been approved by the US Food and Drug Administration (FDA), including schizophrenia, bipolar disorder, irritability associated with autistic disorder, and Tourette disorder.5,6,7,8,9 However, much of the increase has been associated with non–FDA-indicated prescribing, most commonly, attention-deficit/hyperactivity disorder (ADHD).2,3,10,11\n\nAntipsychotic medications can have significant adverse effects in youths. With prolonged exposure, these medications frequently cause adverse metabolic effects, including weight gain, hyperlipidemia, and increased risk of type 2 diabetes.2,12,13 Recent evidence further suggests that antipsychotic treatment in youths is associated with an increased risk of unexpected death.14\n\nPublic and professional concern over the safety of antipsychotic use in young people has led to policies aimed at reducing use of these medications. Policy interventions have targeted absolute reductions in antipsychotic prescribing with less consideration of the clinical characteristics of patients treated with antipsychotics. As of 2014, most states had implemented prior authorization policies for use of antipsychotics in children in their Medicaid programs,15,16 with varying age limitations. These policies have lowered overall antipsychotic use in young children,17 although little is known about the clinical characteristics of young patients who are treated with antipsychotics in community practice.\n\nNearly half of all non–FDA-indicated antipsychotic medication use in young people is for individuals with ADHD diagnoses, with or without other mental health diagnoses.2,18 Yet, ADHD alone is not an evidence-supported indication for antipsychotic medications. Furthermore, little is known about which youths with ADHD are most likely to be treated with antipsychotic medications. Mental health comorbidity is one potential factor associated with antipsychotic treatment in youths with ADHD. Among Medicaid beneficiaries, youths treated with antipsychotics are often diagnosed with depression, oppositional defiant disorder (ODD), or conduct disorder (CD).19 Although depression is not an evidence-supported indication for antipsychotic treatment in youths, some evidence supports the effectiveness of risperidone for treatment of ODD or CD in stimulant-resistant youths with ADHD.19,20,21,22,23,24,25,26,27\n\nThe prevalence of antipsychotic use in youths following a new ADHD diagnosis is not known. Questions also exist regarding the extent to which comorbid mental disorders are associated with antipsychotic treatment in youths with ADHD. In addition, the frequency with which young people with ADHD receive antipsychotic medications before a trial of stimulants is not known. Closing these knowledge gaps will help to focus quality-of-care efforts aimed at safe and judicious antipsychotic prescribing.\n\nWe analyzed claims records of commercially insured youths, aged 3 to 24 years, with a new diagnosis of ADHD. Patients recently diagnosed with conditions for which antipsychotics have an FDA-approved indication (schizophrenia, bipolar disorder, autism spectrum disorder, and Tourette disorder) were excluded from the cohort. To better understand antipsychotic prescribing in this population, this study (1) determined the prevalence of antipsychotic use over the following year, (2) evaluated the associations between clinical and demographic factors and antipsychotic prescribing, and (3) examined the frequency with which stimulant treatment preceded antipsychotic treatment in the first year following a new ADHD diagnosis. Before conducting the analyses, we hypothesized that males and older youths would have higher rates of antipsychotic treatment. We further anticipated that most youths with ADHD who initiated antipsychotic medications would be diagnosed with comorbid, evidence-supported clinical diagnoses (ie, ODD or CD), and would fill stimulant prescriptions before initiating antipsychotic medications.\n\nMethods\nData Source\nData were obtained from the Truven Health MarketScan database of commercially insured individuals from January 1, 2010, to December 31, 2015. This database comprises medical and prescription drug data for more than 115 million enrollees, including demographic characteristics, outpatient and inpatient service codes, diagnostic codes, and detailed pharmacy files.28 The data were deidentified and the study was determined to be exempt from human subjects review by the Rutgers University Institutional Review Board. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.\n\nStudy Design, Participants, and Cohort Assembly\nWe examined records for youths with a new ADHD diagnosis (International Classification of Diseases, Ninth Revision (code 314.xx), and International Statistical Classification of Diseases, 10th Revision (code F90.xx), aged 3 to 24 years, after at least 120 days without an ADHD diagnosis. This 4-month period was chosen because youths with ADHD often are not seen by clinicians during summer months.29 Youths were excluded if they had been prescribed an antipsychotic or stimulant or had received a diagnosis with an indication for an antipsychotic medication (schizophrenia, bipolar disorder, autistic spectrum disorder, and Tourette disorder) in the previous 6 months. This process excluded 4555 youths (2.4% of the total sample). In addition, we required 12 months of continuous health care enrollment following the initial ADHD diagnosis.\n\nClinical and Demographic Characteristics\nBackground Characteristics\nYouths were characterized by sex, age at ADHD diagnosis (3-5, 6-12, 13-18, 19-24 years), other mental health clinical diagnoses (depression, substance use, anxiety, self-harm and/or suicidal ideation, developmental disability, ODD, and CD) and recent mental health treatment, including inpatient care, being seen by a psychiatrist, and other psychopharmacologic treatments during the 180 days before the initial ADHD diagnosis (eTable in the Supplement).\n\nDiagnoses\nBipolar disorder, schizophrenia, and psychotic/delusional disorders, autism spectrum disorder, tic disorders, and Tourette disorder were considered as FDA-indicated diagnoses for antipsychotic treatment (eTable in the Supplement). Given the evidence of efficacy for risperidone in the treatment of ODD and CD, we considered these disorders to be evidence-supported diagnoses.20,21,22,23,24,25,26,27\n\nStatistical Analysis\nThe analysis was conducted in 5 stages between November 1, 2018, and May 30, 2019. We first examined the background (pre-ADHD diagnosis), clinical, and demographic characteristics of youths who did and did not receive an antipsychotic medication during the 12 months following the initial ADHD diagnosis. We examined the incidence of antipsychotic treatment in the year following a new ADHD diagnosis. Unadjusted and age- and sex-adjusted logistic regressions evaluated the associations of each clinical and demographic characteristic with antipsychotic treatment during the 12-month follow-up period.\n\nSecond, to characterize stimulant treatment before antipsychotic initiation, we calculated the percentages of youths who received stimulant prescriptions before antipsychotic initiation among youths initiating antipsychotic medications overall and stratified by sex and age group. Stimulant treatment was defined as no stimulant, only 1 stimulant class (methylphenidate or amphetamine derivative), or both classes (methylphenidate and amphetamine derivative) during the period between new a ADHD diagnosis and antipsychotic initiation.\n\nThird, we examined the first antipsychotic initiated for the cohort who received treatment with antipsychotics. We calculated percentages for each agent and mean (SD) number of antipsychotic prescriptions during the 180-day follow-up period.\n\nFourth, restricted to the antipsychotic-treated cohort, we examined percentages of youths who received an FDA-indicated diagnosis in the year following new ADHD diagnosis (post-ADHD diagnosis) and percentages of youths who received evidence-supported diagnoses in the 6 months before and 12 months after the new ADHD diagnosis. These results were then stratified by age group.\n\nFifth, we performed a subgroup analysis of preschool or very young children (aged 3-5 years) from the initial cohort, using the same variables and adding neurodevelopmental disorders (eTable in the Supplement). Sixth, to assess time to antipsychotic treatment after a new ADHD diagnosis, a Kaplan-Meier survival analysis was performed for each age group (eFigure in the Supplement). Findings were considered significant at 2-tailed unpaired P < .05. All analyses were completed with SAS, version 7.15 HF7 (SAS Institute Inc).\n\nResults\nOf the 187 563 youths included in the study, 114 305 (60.9%) were male, with a mean (SD) age of 13.74 (5.61) years. Within 1 year of a new ADHD diagnosis, antipsychotic medications were initiated by 4869 of 187 563 youths (2.6%; 95% CI, 2.5%-2.7%). The prevalence of antipsychotic treatment was 4.3% (95% CI, 3.9%-4.7%) for very young children (3-5 years), 2.0% (95% CI, 1.9%-2.1%) for older children (6-12 years), 3.2% (95% CI, 3.0%-3.3%) for adolescents (13-18 years), and 2.4% (95% CI, 2.3%-2.6%) for young adults (19-24 years). Overall, antipsychotic initiators were more likely to be male (114 305 [60.9%]); adolescent (13-18 years); recently diagnosed with comorbid mental health conditions, with the most frequent being anxiety (5.8%; 95% CI, 5.5%-6.2%); and recent admission for inpatient mental health treatment (17.6%; 95% CI, 15.3%-20.0%). Antipsychotic initiation was associated with self-harm and/or suicidal ideation (adjusted odds ratio [aOR], 7.5; 95% CI, 5.9-9.6), ODD diagnosis (aOR, 4.4; 95% CI, 3.9-4.9), substance use disorder (aOR, 4.0; 95% CI, 3.6-4.5), and inpatient mental health care (aOR, 7.9; 95% CI, 6.7-9.3) in the preceding 6 months (Table 1 and eFigure in the Supplement).\n\nTable 1. Antipsychotic Treatment of Youths in the Year Following a New ADHD Diagnosisa\nGroupsb\tNo. (%)\tAntipsychotic Treatment, % (95% CI) (n = 4342)\taOR (95% CI)c\t\nTotal\t187 563\t2.6 (2.5-2.7)\tNA\t\nAge, y\t\t\t\t\n 3-5\t10 125 (54.0)\t4.3 (3.9-4.7)\t2.2 (1.9-2.4)\t\n 6-12\t72 126 (38.5)\t2.0 (1.9-2.1)\t1.0\t\n 13-18\t58 166 (31.0)\t3.2 (3.0-3.3)\t1.6 (1.5-1.7)\t\n 19-24\t47 146 (25.1)\t2.4 (2.3-2.6)\t1.2 (1.1-1.3)\t\nSex\t\t\t\t\n Male\t114 305 (60.9)\t2.7 (2.6-2.8)\t1.1 (1.0-1.1)\t\n Female\t73 258 (39.1)\t2.5 (2.4-2.6)\t1 [Reference]\t\nComorbid MH conditiond\t\t\t\t\n Oppositional defiant disorder\t3269 (1.7)\t10.1 (9.1-11.1)\t4.4 (3.9-4.9)\t\n Conduct disorder\t5113 (2.7)\t6.5 (5.8-7.2)\t2.7 (2.4-3.0)\t\n Anxiety disorder\t17 261 (9.2)\t5.8 (5.5-6.2)\t2.7 (2.5-2.9)\t\n Self-harm and/or suicidal ideation\t454 (0.2)\t17.4 (13.9-20.9)\t7.5 (5.9-9.6)\t\n Depression disorders\t12 573 (6.7)\t8.0 (7.6-8.5)\t4.0 (3.7-4.3)\t\n Substance use disorder\t3851 (2.1)\t9.1 (8.2-10.0)\t4.0 (3.6-4.5)\t\n Developmental disability\t210 (0.01)\t8.6 (4.8-12.4)\t3.6 (2.2-5.8)\t\nMH conditions, No.\t\t\t\t\n 0\t152 625 (81.4)\t1.7 (1.7-1.8)\t1 [Reference]\t\n 1\t28 174 (15.0)\t5.3 (5.1-5.6)\t3.2 (3.0-3.4)\t\n 2\t5876 (3.1)\t9.7 (8.9-10.4)\t6.1 (5.5-6.7)\t\n ≥3\t888 (0.5)\t17.1 (14.6-19.6)\t11.5 (9.6-13.8)\t\nMH treatment\t\t\t\t\n Inpatient care\t1016 (0.5)\t17.6 (15.3-20.0)\t7.9 (6.7-9.3)\t\n Treated by psychiatrist\t25 866 (13.8)\t5.9 (5.6-6.2)\t2.9 (2.8-3.1)\t\n Antidepressants\t19 296 (10.3)\t7.4 (7.0-7.7)\t4.1 (3.8-4.4)\t\n Mood stabilizers\t3391 (1.8)\t9.6 (8.6-10.5)\t4.2 (3.7-4.7)\t\n Hypnotics\t5408 (2.9)\t7.0 (6.4-7.7)\t3.2 (2.8-3.6)\t\nAbbreviations: ADHD, attention-deficit/hyperactivity disorder; aOR, adjusted odds ratio; MH, mental health; NA, not applicable.\n\na 2010-2015, MarketScan Data.\n\nb Characteristics present within 180 days before a new ADHD diagnosis.\n\nc The aOR is adjusted by age and sex.\n\nd Groups are not exclusive.\n\nAmong youths who initiated antipsychotic medications, 47.9% (95% CI, 46.5%-49.3%) did not receive a stimulant prescription between their ADHD diagnosis and antipsychotic initiation. Approximately half of the youths (43.8%; 95% CI, 42.4%- 45.1%) who were treated with antipsychotics were prescribed 1 stimulant and 8.4% (95% CI, 7.6%-9.1%) were prescribed methylphenidate or a methylphenidate derivative and an amphetamine derivative before antipsychotic initiation (Table 2).\n\nTable 2. Antipsychotic Treatment in Youths With ADHD Who Received Stimulant Treatment Before Antipsychotic Initiationa,b\nGroup\tNo.\tStimulant, % (95% CI)c,d\t\nNone\t1 Class\tBoth Classes\t\nTotal\t4869\t47.9 (46.5-49.3)\t43.8 (42.4-45.1)\t8.4 (7.6-9.1)\t\nSex\t\t\t\t\t\n Male\t3032\t47.8 (46.0-49.6)\t43.5 (41.7-45.2)\t8.7 (7.7-9.8)\t\n Female\t1837\t48.1 (45.8-50.4)\t44.2 (41.9-46.5)\t7.7 (6.5-9.0)\t\nAge, y\t\t\t\t\t\n 3-5\t432\t38.4 (33.8-43.0)\t44.9 (40.2-49.6)\t16.7 (13.2-20.2)\t\n 6-12\t1459\t46.7 (44.1-49.2)\t42.2 (39.6-44.7)\t11.2 (9.6-12.8)\t\n 13-18\t1832\t52.7 (50.4-55.0)\t41.0 (38.7-43.3)\t6.3 (5.2-7.5)\t\n 19-24\t1146\t45.4 (42.5-48.3)\t49.7 (46.8-52.6)\t4.9 (3.6-6.1)\t\nAbbreviation: ADHD, attention-deficit/hyperactivity disorder.\n\na 2010-2015, MarketScan Data.\n\nb Antipsychotic prescription during the 365 days following a new diagnosis of ADHD.\n\nc Presence or absence of any psychostimulant (methylphenidate or amphetamine derivate) on or before the first antipsychotic prescription.\n\nd Classes of the medications were methylphenidate and amphetamine derivative.\n\nTable 3 presents the percentage of initial antipsychotic agents prescribed and the mean (SD) number of prescriptions. Risperidone (37.8%; mean [SD], 4.0 [3.5]), aripiprazole (32.0%; 3.6 [2.9]), and quetiapine (20.7%; 3.3 [3.0]) were the most commonly prescribed agents.\n\nTable 3. Initial Antipsychotic Prescriptions for Study Perioda\nAntipsychotic Medicationb\tPrescriptions (n=4869)\t\n%\tMean (SD)\t\nAll antipsychotics\t100\t4.1 (3.5)\t\nRisperidone\t37.8\t4.0 (3.5)\t\nHaloperidol\t0.5\t2.4 (2.1)\t\nQuetiapine\t20.7\t3.3 (3.0)\t\nAripiprazole\t32.0\t3.6 (2.9)\t\nOlanzapine\t4.0\t2.5 (2.3)\t\nAll other antipsychotics\t5.0\t2.7 (2.7)\t\nAbbreviations: ADHD, attention-deficit/hyperactivity disorder.\n\na 2010-2015 MarketScan Data (youths with new diagnosis of ADHD and antipsychotic prescription).\n\nb First antipsychotic prescription after diagnosis.\n\nBy the end of the follow-up year, 2565 of 19 990 youths (52.7%; 95% CI, 51.3%-54.1%) treated with antipsychotics had received either a diagnosis for which antipsychotics are FDA indicated in youths (35.1%; 95% CI, 33.8%-36.5%) or had received a clinical diagnosis for which there is evidence of antipsychotic efficacy in youths (26.9%; 95% CI, 25.6%-28.1%) (Table 4).\n\nTable 4. Selected Clinical Diagnoses of Youths Treated With Antipsychotics With ADHDa\nSelected Clinical Diagnosis\tNo. of Patients With ADHD\tYouths Treated with Antipsychotics With ADHD, % (95% CI)\t\nTotal (n = 4869)\tAge, y\t\n3-5 (n = 432)\t6-12 (n = 1459)\t13-18 (n = 1832)\t19-24 (n = 1146)\t\nAny FDA-indicated or evidence-supported diagnosis\t19 990\t52.7 (51.3-54.1)\t63.0 (58.4-67.5)\t58.5 (56.0-61.1)\t51.5 (49.2-53.8)\t43.3 (40.4-46.2)\t\nAny FDA-indicated diagnosisb\t\t35.1 (33.8-36.5)\t25.9 (21.8-30.1)\t30.4 (28.1-32.8)\t37.3 (35.1-39.6)\t41.1 (38.3-44.0)\t\n Bipolar disorder\t2428\t21.2 (20.0-22.3)\t6.3 (4.0-8.5)\t10.5 (8.9-12.1)\t26.5 (24.5-28.5)\t31.9 (29.2-34.6)\t\n Psychosis\t955\t9.2 (8.4-10.0)\t0.9 (0-1.8)\t4.6 (3.5-5.7)\t11.6 (10.2-13.1)\t14.3 (12.3-16.3)\t\n Autism spectrum disorder\t3590\t8.9 (8.1-9.7)\t19.0 (15.3-22.7)\t15.7 (13.8-17.6)\t5.2 (4.2-6.3)\t2.3 (1.4-3.1)\t\n Tourette disorder\t1568\t2.2 (1.8-2.6)\t2.1 (0.7-3.4)\t3.6 (2.6-4.5)\t1.8 (1.2-2.4)\t1.0 (0.4-1.5)\t\nAny evidence-supported diagnosisb,c\t\t26.9 (25.6-28.1)\t50.7 (46.0-55.4)\t40.0 (37.5-42.5)\t24.4 (22.4-26.4)\t5.2 (3.9-6.4)\t\n Oppositional defiant disorder\t6374\t16.1 (15.1-17.2)\t28.7 (24.4-33.0)\t25.9 (23.7-28.2)\t15.0 (13.4-16.7)\t0.8 (0.3-1.3)\t\n Conduct disorder\t8414\t16.1 (15.1-17.1)\t33.6 (29.1-38.0)\t22.0 (19.9-24.1)\t14.6 (13.0-16.2)\t4.5 (3.3-5.6)\t\nAbbreviations: ADHD, attention-deficit/hyperactivity disorder; FDA, US Food and Drug Administration.\n\na 2010-2015 MarketScan Data.\n\nb Groups are not exclusive.\n\nc Includes pre-ADHD diagnosis study period and study year.\n\nA total of 432 of 10 125 (4.3%) very young children (aged 3-5 years) with ADHD were treated with an antipsychotic medication. Compared with those who were not treated with an antipsychotic, those who received an antipsychotic were more likely to have been diagnosed with a neurodevelopment disorder (aOR, 3.9; 95% CI, 1.3-11.2), received inpatient mental health care (aOR, 8.9; 95% CI, 1.7-45.8), and received care from a psychiatrist (aOR, 3.3; 95% CI, 2.7-4.2) (Table 5). The likelihood of antipsychotic treatment in the very young cohort increased with the number of mental health and neurodevelopmental diagnoses they received (1 diagnosis: aOR, 1.9; 95% CI, 1.5-2.4; 2 diagnoses: aOR, 3.7; 95% CI, 2.4-5.7; ≥3 diagnoses: aOR, 6.8; 95% CI, 1.9-24.1).\n\nTable 5. Very Young Children (3-5 Years) Prescribed Antipsychotics in the Year Following ADHD Diagnosis (n = 10 125)a\nCharacteristicb\tAntipsychotic Treatment, No./Total No. (%) \taOR (95% CI)c\t\nTotal\t432/10 125 (4.3)\tNA\t\nSex\t\t\t\n Male\t341/7666 (4.5)\t1.2 (1.0-1.5)\t\n Female\t91/2459 (3.7)\t1 [Reference]\t\nComorbid MH and neurodevelopmental conditionsd\t\t\t\n None\t223/6699 (3.3)\t0.5 (0.4-0.6)\t\n Oppositional defiant disorder\t45/441 (10.2)\t2.7 (2.0-3.8)\t\n Conduct disorder\t75/1040 (7.2)\t1.9 (1.5-2.4)\t\n Anxiety disorder (any)\t33/413 (8.0)\t2.1 (1.4-3.0)\t\n Depression disorders (any)\t5/56 (8.9)\t2.2 (0.9-5.6)\t\n Neurodevelopmental disorder\t4/28 (14.3)\t3.9 (1.3-11.2)\t\n Developmental disability\t1/21 (4.8)\t1.1 (0.2-8.5)\t\nNo. of MH or neurodevelopmental conditions\t\t\t\n 0\t300/8358 (3.6)\t1 [Reference]\t\n 1\t105/1551 (6.8)\t1.9 (1.5-2.4)\t\n 2\t24/201 (11.9)\t3.7 (2.4-5.7)\t\n ≥3\t3/15 (20.0)\t6.8 (1.9-24.1)\t\nTreatment\t\t\t\n MH inpatient care\t2/7 (28.6)\t8.9 (1.7-45.8)\t\n Treated by psychiatrist\t116/1076 (10.8)\t3.3 (2.7-4.2)\t\n Treated by neurologist\t11/353 (3.1)\t0.7 (0.4-1.3)\t\nAbbreviatons: ADHD, attention/deficit hyperactivity disorder; aOR, adjusted odds ratio; MH, mental health; NA, not applicable.\n\na 2010-2015 MarketScan Data.\n\nb Characteristics present within 180 days before a new ADHD diagnosis.\n\nc The aOR is adjusted for sex.\n\nd Groups are not mutually exclusive.\n\nThe eFigure in the Supplement displays the time to antipsychotic initiation for ADHD youths by age group, with the most rapid increase occurring during the first 30 days.\n\nDiscussion\nAntipsychotic medications were prescribed for 2.6% of commercially insured youths in the year following a new clinical diagnosis of ADHD without a recent diagnosis that has an FDA indication for antipsychotic treatment. Factors for antipsychotic treatment included a wide range of comorbid psychiatric diagnoses. Conduct disorder and ODD were factors associated with antipsychotic treatment. However, only approximately half of the antipsychotic treated patients received diagnoses (FDA-indicated, CD or ODD) with evidence of clinical benefits from antipsychotics during the pre- or post-ADHD diagnosis period. These data reveal the extent to which antipsychotics are prescribed to young people with ADHD and raise concerns regarding potential non–evidence-based antipsychotic use and underuse of stimulant medications.\n\nPrevalence of Antipsychotic Use in ADHD\nThe percentage of youths with a new ADHD diagnosis who were treated with an antipsychotic without an FDA indication (2.6%) was greater than the overall annual prevalence of antipsychotic treatment among youths in the general population (0.6%).4,30,31 Despite public policies and interventions aimed at reducing off-label antipsychotic medication prescriptions for youths,32,33 young people diagnosed with ADHD appear to have an increased likelihood of filling antipsychotic prescriptions. Professional statements and practice guidelines released by the American Psychiatric Association and the American Academy of Child and Adolescent Psychiatry have encouraged clinicians to reduce use of antipsychotic medications in youths without an approved or evidence-supported indication.23,34 Although these efforts may have reduced off-label prescription of antipsychotic medications to young people overall, their use among young people with ADHD remains significant.\n\nAge-Related Changes in Antipsychotic Use\nThe demographic profile of antipsychotic prescribing among youths with ADHD diagnoses is consistent with patterns observed in the general population of young people. Within the general population, the likelihood of antipsychotic use is also higher among male than female individuals and adolescents than children.2 This pattern may be associated with the use of antipsychotics in the management of impulsive and aggressive behaviors in youths with ADHD.18,20 After adolescence, decreases in the fraction of antipsychotic prescribing for young adults with ADHD have previously been described and are consistent with treatment of conduct problems that peak in adolescence.35 This decline is potentially associated with suppression of aggressive behaviors and improved impulse control in late adolescence from maturation of prefrontal gray matter and proliferation of white matter tracts.36,37\n\nThe flattest antipsychotic initiation curve occurs in school-aged youths (6-12 years). Based on new incidence, this is the age group at highest risk for initial ADHD presentations and when most medications are first used.18 A possible explanation of a flat curve is that symptoms are being addressed through the availability of nonpharmacologic, school-based interventions available to elementary school children.38 However, because these interventions are not recorded through insurance databases, we are unable to measure this.\n\nDiagnostic Factors Associated With Antipsychotic Use\nAmong youths with ADHD, several clinically diagnosed mental disorder comorbidities have been associated with an elevated likelihood for antipsychotic treatment. In youths with ADHD, many of these comorbidities are related to poorer response to stimulant treatment and adverse outcomes.39,40,41 Although antipsychotics could be prescribed because of incomplete response to other treatments, many of these conditions do not have empirical evidence supporting antipsychotic treatment. Outside of FDA indications, only ODD, CD, and aggression in ADHD have clinical experimental evidence to support the use of antipsychotics and only approximately half of the cohort of youths with ADHD who received antipsychotics had 1 or more of these clinical diagnoses.20,21,22,23,24,25,26,27\n\nRecent inpatient mental health care was associated with antipsychotic treatment. Symptom severity thresholds for receiving acute inpatient mental health care are often high, particularly for severe ADHD.42,43,44 Young people whose symptoms have led to hospitalization likely have more complex clinical presentations than their peers who are not receiving antipsychotics. However, the effectiveness of antipsychotics for the treatment of severe uncomplicated ADHD has not been established. The youths with ADHD who were prescribed an antipsychotic but lacked an ODD or CD diagnosis could also have aggression or represent poor community pharmacologic management of ADHD.\n\nAntipsychotic treatment was proportionately highest among very young children (4.3%). This group accounts for approximately a quarter of a percent of the total ADHD cohort, with very young children accounting for a small percentage of ADHD-treated youths. These children were more likely to have neurodevelopmental disorders than their age-matched peers who were not treated with antipsychotic medications and received high rates of inpatient mental health care. Antipsychotic treatment may be reserved for children with greater symptom severity. While ADHD uncommonly presents in very young children, those with ADHD tend to have severe symptoms and relatively poor response rates to stimulants.45,46 Furthermore, although nonpharmacologic treatment is generally regarded as first line in this age group, evidence-based psychosocial interventions, such as parenting training and parent-child interaction therapy, are not widely available.47\n\nFewer than half of the youths received a stimulant before their antipsychotic and fewer than 1 in 10 received a methylphenidate and amphetamine derivative. Antipsychotics are only potentially indicated in youths with ADHD after treatment trials of both methylphenidate and mixed amphetamine salts.21,48 This treatment pattern raises concerns that some youths with ADHD may be treated with antipsychotics prematurely, before receiving trials of adequate dose and duration of both classes of stimulants, potentially unnecessarily exposing them to antipsychotic treatment.\n\nRisperidone was the most commonly first prescribed antipsychotic for youths with ADHD. This practice is consistent with recommendations. Risperidone has the strongest evidence base for off-label use in youths, particularly in ODD, CD, and aggression.21,22,23,24,25,26,27 However, nearly two-thirds of the antipsychotic-treated sample initially were treated with other antipsychotics that either have negative trials or lack trials to support their use in ADHD.25,26,27\n\nA wide range of clinical characteristics, including mental disorder comorbidities, and inpatient mental health care are associated with antipsychotic treatment in youths with ADHD. Aggression, which is common in ADHD and not always responsive to stimulant medications, has been hypothesized to account for much of the off-label use of antipsychotics in youths with ADHD.2,49,50 Consistent with this hypothesis, antipsychotic-treated youths with ADHD had clinical characteristics commonly associated with aggression in ADHD, such as inpatient hospitalization and a higher prevalence of comorbid disorders.42,43,44,51,52,53 However, few youths treated with antipsychotics with ADHD received the evidence-indicated trials of 2 stimulants before an antipsychotic.\n\nCurrent therapy management efforts in both private and publicly insured populations have been focused on curbing antipsychotic use in youths with less attention devoted to the clinical rationale for use. These policies have been particularly widely applied to Medicaid populations,15 including telephone consultations with psychiatrists, letters to prescribers, and age-related prior authorization policies.15 A greater understanding of the clinical rationale and timing of antipsychotic treatment of youths with ADHD might help to guide more clinically sensitive policies to regulate antipsychotic use.\n\nThis analysis was limited to commercially insured children. Much of the prior work on antipsychotic use in children has focused on Medicaid populations. Important socioeconomic and health differences exist between commercially insured and Medicaid-insured populations.54,55 Yet some aspects of our sample resemble those in antipsychotic-treated Medicaid youths. For example, similar to analyses of Medicaid samples, our sample was predominantly male and had similar rates of CD, anxiety, and depression diagnoses.14,19,56,57\n\nLimitations\nThis analysis has several limitations. First, diagnoses were based on clinical judgment—not structured interviews. Second, we were unable to examine antipsychotic treatment following the first lifetime diagnosis of ADHD. Patterns of antipsychotic treatment may be different following initial and new episodes of clinical ADHD diagnosis. Third, we examined commercially insured individuals; different results might be obtained from Medicaid beneficiaries in whom antipsychotic treatment is more common.57 Although Medicaid programs have implemented management programs to limit antipsychotic use, few commercial insurance programs have followed suit. Nevertheless, these programs, along with medical society guidelines,48 may be associated with diagnostic and prescribing practices for commercially insured patients. Fourth, several potentially important factors to understanding antipsychotic treatment patterns, such as race/ethnicity, family circumstances, and home environment, were unavailable in the data set. Furthermore, we were unable to measure symptoms that might have provided a clinical rationale, such as severe aggression, for antipsychotic treatment. In addition, data on medication use were based on filled prescriptions rather than observed medication consumption.\n\nConclusions\nAmong diagnostic groups in young people, ADHD may account for the largest share of antipsychotic treatment.2,3,10,11 Our results suggest associations between comorbid psychiatric diagnoses and the use of antipsychotic treatment in youths with ADHD. While some of these young people were diagnosed with conditions for which antipsychotics have some evidence of clinical effectiveness, many others were not. In view of the serious safety risks posed by antipsychotic treatment of young people, these patterns highlight the importance of remaining vigilant concerning antipsychotic medication prescribing patterns in the community treatment of ADHD.\n\nSupplement. eTable. Coding For MarketScan Data (2010-2015)\n\neFigure. Survival Curve Comparing Age Group to Time of Antipsychotic Initiation in Youths With a New ADHD Diagnosis\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Olfson M , Blanco C , Wang S , Laje G , Correll CU \nNational trends in the mental health care of children, adolescents, and adults by office-based physicians . JAMA Psychiatry . 2014 ;71 (1 ):-. doi:10.1001/jamapsychiatry.2013.3074 \n24285382 \n2 Olfson M , King M , Schoenbaum M \nTreatment of young people with antipsychotic medications in the United States . JAMA Psychiatry . 2015 ;72 (9 ):867 -874 . doi:10.1001/jamapsychiatry.2015.0500 \n26132724 \n3 Olfson M , Blanco C , Liu SM , Wang S , Correll CU \nNational trends in the office-based treatment of children, adolescents, and adults with antipsychotics . Arch Gen Psychiatry . 2012 ;69 (12 ):1247 -1256 . doi:10.1001/archgenpsychiatry.2012.647 \n22868273 \n4 Hales CM , Kit BK , Gu Q , Ogden CL \nTrends in prescription medication use among children and adolescents—United States, 1999-2014 . JAMA . 2018 ;319 (19 ):2009 -2020 . doi:10.1001/jama.2018.5690 29800213 \n5 Marcus RN , Owen R , Kamen L , \nA placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder . J Am Acad Child Adolesc Psychiatry . 2009 ;48 (11 ):1110 -1119 . doi:10.1097/CHI.0b013e3181b76658 \n19797985 \n6 McCracken JT , McGough J , Shah B , ; Research Units on Pediatric Psychopharmacology Autism Network \nRisperidone in children with autism and serious behavioral problems . N Engl J Med . 2002 ;347 (5 ):314 -321 . doi:10.1056/NEJMoa013171 \n12151468 \n7 Findling RL , Robb A , Nyilas M , \nA multiple-center, randomized, double-blind, placebo-controlled study of oral aripiprazole for treatment of adolescents with schizophrenia . Am J Psychiatry . 2008 ;165 (11 ):1432 -1441 . doi:10.1176/appi.ajp.2008.07061035 \n18765484 \n8 Tohen M , Kryzhanovskaya L , Carlson G , \nOlanzapine versus placebo in the treatment of adolescents with bipolar mania . Am J Psychiatry . 2007 ;164 (10 ):1547 -1556 . doi:10.1176/appi.ajp.2007.06111932 \n17898346 \n9 Findling RL , Nyilas M , Forbes RA , \nAcute treatment of pediatric bipolar I disorder, manic or mixed episode, with aripiprazole: a randomized, double-blind, placebo-controlled study . J Clin Psychiatry . 2009 ;70 (10 ):1441 -1451 . doi:10.4088/JCP.09m05164yel \n19906348 \n10 Alexander GC , Gallagher SA , Mascola A , Moloney RM , Stafford RS \nIncreasing off-label use of antipsychotic medications in the United States, 1995-2008 . Pharmacoepidemiol Drug Saf . 2011 ;20 (2 ):177 -184 . doi:10.1002/pds.2082 \n21254289 \n12 Matone M , Localio R , Huang Y-S , dosReis S , Feudtner C , Rubin D \nThe relationship between mental health diagnosis and treatment with second-generation antipsychotics over time: a national study of US Medicaid-enrolled children . Health Serv Res . 2012 ;47 (5 ):1836 -1860 . doi:10.1111/j.1475-6773.2012.01461.x \n22946905 \n13 Correll CU , Lencz T , Malhotra AK \nAntipsychotic drugs and obesity . Trends Mol Med . 2011 ;17 (2 ):97 -107 . doi:10.1016/j.molmed.2010.10.010 \n21185230 \n14 Galling B , Correll CU \nDo antipsychotics increase diabetes risk in children and adolescents? \nExpert Opin Drug Saf . 2015 ;14 (2 ):219 -241 . doi:10.1517/14740338.2015.979150 \n25480466 \n15 Ray WA , Stein CM , Murray KT , \nAssociation of antipsychotic treatment with risk of unexpected death among children and youths . JAMA Psychiatry . JAMA Psychiatry . 2019 ;76 (2 ):162 -171 . doi:10.1001/jamapsychiatry.2018.3421 30540347 \n16 Schmid I , Burcu M , Zito JM \nMedicaid prior authorization policies for pediatric use of antipsychotic medications . JAMA . 2015 ;313 (9 ):966 -968 . doi:10.1001/jama.2015.0763 \n25734740 \n17 Melvin KE , Hart JC , Sorvig RD \nSecond-generation antipsychotic prescribing patterns for pediatric patients enrolled in West Virginia Medicaid . Psychiatr Serv . 2017 ;68 (10 ):1061 -1067 . doi:10.1176/appi.ps.201600489 \n28566023 \n18 Zito JM , Burcu M , McKean S , Warnock R , Kelman J \nPediatric use of antipsychotic medications before and after Medicaid peer review implementation . JAMA Psychiatry . 2018 ;75 (1 ):100 -103 . doi:10.1001/jamapsychiatry.2017.3493 \n29141077 \n19 Sultan RS , Correll CU , Schoenbaum M , King M , Walkup JT , Olfson M \nNational patterns of commonly prescribed psychotropic medications to young people . J Child Adolesc Psychopharmacol . 2018 ;28 (3 ):158 -165 . doi:10.1089/cap.2017.0077 29376743 \n20 Pathak P , West D , Martin BC , Helm ME , Henderson C \nEvidence-based use of second-generation antipsychotics in a state Medicaid pediatric population, 2001-2005 . Psychiatr Serv . 2010 ;61 (2 ):123 -129 . doi:10.1176/ps.2010.61.2.123 \n20123816 \n21 Pan P-Y , Fu A-T , Yeh C-B \nAripiprazole/methylphenidate combination in children and adolescents with disruptive mood dysregulation disorder and attention-deficit/hyperactivity disorder: an open-label study . J Child Adolesc Psychopharmacol . 2018 ;28 (10 ):682 -689 . doi:10.1089/cap.2018.0068 \n30148656 \n22 Gurnani T , Ivanov I , Newcorn JH \nPharmacotherapy of aggression in child and adolescent psychiatric disorders . J Child Adolesc Psychopharmacol . 2016 ;26 (1 ):65 -73 . doi:10.1089/cap.2015.0167 \n26881859 \n23 Pringsheim T , Hirsch L , Gardner D , Gorman DA \nThe pharmacological management of oppositional behaviour, conduct problems, and aggression in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder: a systematic review and meta-analysis—part 2: antipsychotics and traditional mood stabilizers . Can J Psychiatry . 2015 ;60 (2 ):52 -61 . doi:10.1177/070674371506000203 \n25886656 \n24 Findling RL , Drury SS , Jensen PS AACAP Committee on Quality Issues. Practice parameter for the use of atypical antipsychotic medications in children and adolescents. https://www.aacap.org/App_Themes/AACAP/docs/practice_parameters/Atypical_Antipsychotic_Medications_Web.pdf. Published 2011 . Accessed June 18, 2019.\n25 Armenteros JL , Lewis JE , Davalos M , Arabgol F , Panaghi L , Nikzad V \nRisperidone augmentation for treatment-resistant aggression in attention-deficit/hyperactivity disorder: a placebo-controlled pilot study . J Am Acad Child Adolesc Psychiatry . 2007 ;46 (5 ):558 -565 . doi:10.1097/chi.0b013e3180323354 17450046 \n26 Findling RL , Short EJ , Leskovec T , \nAripiprazole in children with attention-deficit/hyperactivity disorder . J Child Adolesc Psychopharmacol . 2008 ;18 (4 ):347 -354 . doi:10.1089/cap.2007.0124 \n18759644 \n27 Tramontina S , Zeni CP , Ketzer CR , Pheula GF , Narvaez J , Rohde LA \nAripiprazole in children and adolescents with bipolar disorder comorbid with attention-deficit/hyperactivity disorder: a pilot randomized clinical trial . J Clin Psychiatry . 2009 ;70 (5 ):756 -764 . doi:10.4088/JCP.08m04726 19389329 \n28 Kronenberger WG , Giauque AL , Lafata DE , Bohnstedt BN , Maxey LE , Dunn DW \nQuetiapine addition in methylphenidate treatment-resistant adolescents with comorbid ADHD, conduct/oppositional-defiant disorder, and aggression: a prospective, open-label study . J Child Adolesc Psychopharmacol . 2007 ;17 (3 ):334 -347 . doi:10.1089/cap.2006.0012 \n17630867 \n29 Leigh Hansen MSM The Truven Health MarketScan Databases for life sciences researchers. https://truvenhealth.com/Portals/0/Assets/2017-MarketScan-Databases-Life-Sciences-Researchers-WP.pdf. Published March 2017 . Accessed February 12, 2018.\n30 Ibrahim K , Donyai P \nDrug holidays from ADHD medication: international experience over the past four decades . J Atten Disord . 2015 ;19 (7 ):551 -568 . doi:10.1177/1087054714548035 \n25253684 \n31 Froehlich TE , Lanphear BP , Epstein JN , Barbaresi WJ , Katusic SK , Kahn RS \nPrevalence, recognition, and treatment of attention-deficit/hyperactivity disorder in a national sample of US children . Arch Pediatr Adolesc Med . 2007 ;161 (9 ):857 -864 . doi:10.1001/archpedi.161.9.857 \n17768285 \n32 Olfson M , Gameroff MJ , Marcus SC , Jensen PS \nNational trends in the treatment of attention deficit hyperactivity disorder . Am J Psychiatry . 2003 ;160 (6 ):1071 -1077 . doi:10.1176/appi.ajp.160.6.1071 \n12777264 \n33 Vitiello B , Correll C , van Zwieten-Boot B , Zuddas A , Parellada M , Arango C \nAntipsychotics in children and adolescents: increasing use, evidence for efficacy and safety concerns . Eur Neuropsychopharmacol . 2009 ;19 (9 ):629 -635 . doi:10.1016/j.euroneuro.2009.04.008 \n19467582 \n34 Correll CU \nAntipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes . J Am Acad Child Adolesc Psychiatry . 2008 ;47 (1 ):9 -20 . doi:10.1097/chi.0b013e31815b5cb1 \n18174821 \n35 Choosing Wisely American Psychiatric Association. http://www.choosingwisely.org/clinician-lists/american-psychiatric-association-antipsychotics-in-children-or-adolescents/. Updated August 21, 2014. Accessed June 1, 2019. .\n36 Moffitt TE \nAdolescence-limited and life-course-persistent antisocial behavior: a developmental taxonomy .Psychol Rev . 1993 ;100 (4 ):674 -701 . doi:10.1037/0033-295X.100.4.674 \n8255953 \n37 Monahan KC , Steinberg L , Cauffman E , Mulvey EP \nTrajectories of antisocial behavior and psychosocial maturity from adolescence to young adulthood . Dev Psychol . 2009 ;45 (6 ):1654 -1668 . doi:10.1037/a0015862 \n19899922 \n38 Steinberg L \nA social neuroscience perspective on adolescent risk-taking . Dev Rev . 2008 ;28 (1 ):78 -106 . doi:10.1016/j.dr.2007.08.002 \n18509515 \n39 Slade EP \nEffects of school-based mental health programs on mental health service use by adolescents at school and in the community . Ment Health Serv Res . 2002 ;4 (3 ):151 -166 . doi:10.1023/A:1019711113312 \n12385568 \n40 Kessler RC , Adler LA , Berglund P , \nThe effects of temporally secondary co-morbid mental disorders on the associations of DSM-IV ADHD with adverse outcomes in the US National Comorbidity Survey Replication Adolescent Supplement (NCS-A) . Psychol Med . 2014 ;44 (8 ):1779 -1792 . doi:10.1017/S0033291713002419 \n24103255 \n41 Blader JC , Pliszka SR , Jensen PS , Schooler NR , Kafantaris V \nStimulant-responsive and stimulant-refractory aggressive behavior among children with ADHD . Pediatrics . 2010 ;126 (4 ):e796 -e806 . doi:10.1542/peds.2010-0086 \n20837589 \n42 Al Ghriwati N , Langberg JM , Gardner W , \nImpact of mental health comorbidities on the community-based pediatric treatment and outcomes of children with attention deficit hyperactivity disorder . J Dev Behav Pediatr . 2017 ;38 (1 ):20 -28 . doi:10.1097/DBP.0000000000000359 \n27902542 \n43 Souery D , Oswald P , Massat I , ; Group for the Study of Resistant Depression \nClinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study . J Clin Psychiatry . 2007 ;68 (7 ):1062 -1070 . doi:10.4088/JCP.v68n0713 \n17685743 \n44 Martin A , Leslie D \nPsychiatric inpatient, outpatient, and medication utilization and costs among privately insured youths, 1997-2000 . Am J Psychiatry . 2003 ;160 (4 ):757 -764 . doi:10.1176/appi.ajp.160.4.757 \n12668366 \n45 Tossone K , Jefferis E , Bhatta MP, Bilge-Johnson S, Seifert P. Risk factors for rehospitalization and inpatient care among pediatric psychiatric intake response center patients . Child Adolesc Psychiatry Ment Health . 2014 ;8 (1 ):27 . doi:10.1186/1753-2000-8-27 \n25392713 \n46 Greenhill L , Kollins S , Abikoff H , \nEfficacy and safety of immediate-release methylphenidate treatment for preschoolers with ADHD . J Am Acad Child Adolesc Psychiatry . 2006 ;45 (11 ):1284 -1293 . doi:10.1097/01.chi.0000235077.32661.61 \n17023867 \n47 Vitiello B , Lazzaretto D , Yershova K , \nPharmacotherapy of the Preschool ADHD Treatment Study (PATS) children growing up . J Am Acad Child Adolesc Psychiatry . 2015 ;54 (7 ):550 -556 . doi:10.1016/j.jaac.2015.04.004 \n26088659 \n48 Comer JS , Furr JM , Miguel EM , \nRemotely delivering real-time parent training to the home: an initial randomized trial of Internet-delivered parent-child interaction therapy (I-PCIT) . J Consult Clin Psychol . 2017 ;85 (9 ):909 -917 . doi:10.1037/ccp0000230 \n28650194 \n49 Scotto Rosato N , Correll CU , Pappadopulos E , Chait A , Crystal S , Jensen PS ; Treatment of Maladaptive Aggressive in Youth Steering Committee \nTreatment of maladaptive aggression in youth: CERT guidelines II—treatments and ongoing management . Pediatrics . 2012 ;129 (6 ):e1577 -e1586 . doi:10.1542/peds.2010-1361 \n22641763 \n50 Connor DF , Glatt SJ , Lopez ID , Jackson D , Melloni RH Jr \nPsychopharmacology and aggression—I: a meta-analysis of stimulant effects on overt/covert aggression-related behaviors in ADHD . J Am Acad Child Adolesc Psychiatry . 2002 ;41 (3 ):253 -261 . doi:10.1097/00004583-200203000-00004 \n11886019 \n51 Jensen PS , Youngstrom EA , Steiner H , \nConsensus report on impulsive aggression as a symptom across diagnostic categories in child psychiatry: implications for medication studies . J Am Acad Child Adolesc Psychiatry . 2007 ;46 (3 ):309 -322 . doi:10.1097/chi.0b013e31802f1454 \n17314717 \n52 Crystal S , Olfson M , Huang C , Pincus H , Gerhard T \nBroadened use of atypical antipsychotics: safety, effectiveness, and policy challenges . Health Aff (Millwood) . 2009 ;28 (5 ):w770 -w781 . doi:10.1377/hlthaff.28.5.w770 \n19622537 \n53 O’Leary KD , Tintle N , Bromet EJ , Gluzman SF \nDescriptive epidemiology of intimate partner aggression in Ukraine . Soc Psychiatry Psychiatr Epidemiol . 2008 ;43 (8 ):619 -626 . doi:10.1007/s00127-008-0339-8 \n18360731 \n54 Connor DF , Chartier KG , Preen EC , Kaplan RF \nImpulsive aggression in attention-deficit/hyperactivity disorder: symptom severity, co-morbidity, and attention-deficit/hyperactivity disorder subtype . J Child Adolesc Psychopharmacol . 2010 ;20 (2 ):119 -126 . doi:10.1089/cap.2009.0076 \n20415607 \n55 Frakt A , Carroll AE , Pollack HA , Reinhardt U \nOur flawed but beneficial Medicaid program . N Engl J Med . 2011 ;364 (16 ):e31 . doi:10.1056/NEJMp1103168 \n21470001 \n56 Todd J , Armon C , Griggs A , Poole S , Berman S \nIncreased rates of morbidity, mortality, and charges for hospitalized children with public or no health insurance as compared with children with private insurance in Colorado and the United States . Pediatrics . 2006 ;118 (2 ):577 -585 . doi:10.1542/peds.2006-0162 \n16882810 \n57 Bobo WV , Cooper WO , Stein CM , \nAntipsychotics and the risk of type 2 diabetes mellitus in children and youth . JAMA Psychiatry . 2013 ;70 (10 ):1067 -1075 . doi:10.1001/jamapsychiatry.2013.2053 \n23965896 \n58 Crystal S , Mackie T , Fenton MC , \nRapid growth of antipsychotic prescriptions for children who are publicly insured has ceased, but concerns remain . Health Aff (Millwood) . 2016 ;35 (6 ):974 -982 . doi:10.1377/hlthaff.2016.0064 \n27269012\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2574-3805",
"issue": "2(7)",
"journal": "JAMA network open",
"keywords": null,
"medline_ta": "JAMA Netw Open",
"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D001289:Attention Deficit Disorder with Hyperactivity; D000697:Central Nervous System Stimulants; D002648:Child; D002675:Child, Preschool; D015897:Comorbidity; D011307:Drug Prescriptions; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D001523:Mental Disorders; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "101729235",
"other_id": null,
"pages": "e197850",
"pmc": null,
"pmid": "31348506",
"pubdate": "2019-07-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "11886019;12151468;12385568;12668366;12777264;16882810;17023867;17314717;17450046;17630867;17685743;17768285;17898346;18174821;18360731;18509515;18759644;18765484;19389329;19467582;19622537;19797985;19899922;19906348;20123816;20415607;20837589;21185230;21254289;21470001;22641763;22868273;22946905;23965896;24103255;24285382;25253684;25392713;25480466;25734740;25886656;26088659;26132724;26881859;27269012;27902542;28566023;28650194;29141077;29376743;29800213;30148656;30540347;8255953",
"title": "Antipsychotic Treatment Among Youths With Attention-Deficit/Hyperactivity Disorder.",
"title_normalized": "antipsychotic treatment among youths with attention deficit hyperactivity disorder"
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"abstract": "Carbapenem-resistant Klebsiella pneumoniae infection is a major cause of morbidity and mortality after solid-organ transplant and hematopoietic stem cell transplant. Here, we report a 57-year-old man with hepatitis B virus-related decompensated liver cirrhosis, huge splenic artery aneurysm, and hypersplenism who underwent liver transplant from a deceased brain-dead donor. Recipient sputum surveillance showed carbapenem-resistant Klebsiella pneumoniae when he entered the intensive care unit, and combined tigecycline, meropenem, and fosfomycin were administered. At 1 week posttransplant, the recipient's hepatic artery was eroded by disseminated carbapenem-resistant Klebsiella pneumoniae infection, and the patient developed acute kidney injury. Our experience suggests that colonization of carbapenem-producing organisms may be included during surveillance posttransplant and that the infected graft artery must be removed instead of noninfected vessels.",
"affiliations": "From the Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.",
"authors": "Qian|Yongbing|Y|;Zhang|Haomin|H|;Chen|Xiaosong|X|;Zhang|Jianjun|J|;Xia|Qiang|Q|",
"chemical_list": "D015780:Carbapenems",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2018.0384",
"fulltext": null,
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"issn_linking": "1304-0855",
"issue": "18(4)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D015780:Carbapenems; D024881:Drug Resistance, Bacterial; D017809:Fatal Outcome; D006499:Hepatic Artery; D006509:Hepatitis B; D006801:Humans; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D008103:Liver Cirrhosis; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012422:Rupture, Spontaneous; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "529-532",
"pmc": null,
"pmid": "31424357",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Graft Hepatic Artery Rupture Due to Carbapenem-Resistant Klebsiella pneumoniae Infection After Liver Transplant.",
"title_normalized": "graft hepatic artery rupture due to carbapenem resistant klebsiella pneumoniae infection after liver transplant"
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"companynumb": "CN-ACCORD-153053",
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"abstract": "Respiratory complaints alone or in association with musculoskeletal complaints can be the predominant presenting feature of antisynthetase syndrome. Therefore, antibodies to cellular antigens should be evaluated in such clinical settings.",
"affiliations": "Departments of Physiology and Pathophysiology School of Medicine National and Kapodistrian University of Athens Athens Greece.;Chair Medical Sciences/Immunology Athens Academy Athens Greece.",
"authors": "Mavragani|Clio P|CP|https://orcid.org/0000-0002-8214-7406;Moutsopoulos|Haralampos M|HM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.2778",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.2778\nCCR32778\nClinical Image\nClinical Images\nA case of antisynthetase syndrome\nMAVRAGANI and MOUTSOPOULOSMavragani Clio P. https://orcid.org/0000-0002-8214-7406\n1\nkmauragan@med.uoa.gr Moutsopoulos Haralampos M. \n2\n \n1 \nDepartments of Physiology and Pathophysiology\nSchool of Medicine\nNational and Kapodistrian University of Athens\nAthens\nGreece\n\n\n2 \nChair Medical Sciences/Immunology\nAthens Academy\nAthens\nGreece\n\n* Correspondence\n\nClio P. Mavragani, Department of Physiology, School of Medicine, University of Athens, M.Asias 75, 11527 Athens, Greece.\n\nEmail: kmauragan@med.uoa.gr\n\n03 6 2020 \n8 2020 \n8 8 10.1002/ccr3.v8.81586 1587\n21 8 2019 16 1 2020 05 2 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nRespiratory complaints alone or in association with musculoskeletal complaints can be the predominant presenting feature of antisynthetase syndrome. Therefore, antibodies to cellular antigens should be evaluated in such clinical settings.\n\nRespiratory complaints alone or in association with musculoskeletal complaints can be the predominant presenting feature of antisynthetase syndrome. Therefore, antibodies to cellular antigens should be evaluated in such clinical settings.\n\n\nantibodies against cellular antigensantisynthetase syndromeinterstitial lung diseaseRaynaud's source-schema-version-number2.0cover-dateAugust 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.8 mode:remove_FC converted:28.08.2020\n\n\nMavragani \nCP \n, \nMoutsopoulos \nH \n. A case of antisynthetase syndrome\n. Clin Case Rep . 2020 ;8 :1586 –1587\n. 10.1002/ccr3.2778\n==== Body\nA 54‐year‐old man presented with a recent onset of arthralgias in both wrists and knees. System review revealed Raynaud's phenomenon and dry cough started approximately 3 months ago. Physical examination was significant for left knee arthritis, swollen hands, flat violaceous papules mainly on the dorsum of the metacarpophalangeal joints (Figure 1A), crackles over the left lower lung field, and 4/5 motor strength in upper extremities. Laboratory testing disclosed mild leucopenia with CK and aldolase levels being slightly elevated. High‐resolution computed tomography disclosed ground glass opacities, resulting in obscuration of the vascular outlines and adjacent airway walls, most likely consistent with organizing pneumonia (OP) (Figure 1B). Bronchoalveolar lavage revealed a lymphocytic exudate with cultures for common bacteria, fungi, and mycobacteria reported negative. Patient refused lung biopsy. Immunological testing was significant for positive ANA (titer 1/1280, cytoplasmic pattern), autoantibodies against Ro52 and Jo‐1 t‐RNA synthetase. The patient was started on methylprednisolone 0.4 mg/kg body weight and mycophenolate mofetil at a dose of 2 gr daily. This case highlights the significance of evaluating serum autoantibodies in patients presenting with subtle autoimmune manifestations not fulfilling classification criteria of an autoimmune disease.\n1\n Moreover, the unusual presentation of antisynthetase syndrome as OP‐like picture is emphasized.\n2\n\n\n\nFigure 1 A, Flat violaceous papules on the dorsum of the metacarpophalangeal joints. B, High‐resolution computed tomography disclosed ground glass opacities likely consistent with organizing pneumonia\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nCPM: wrote the initial draft, participated in reviewing the literature, interpretation of clinical findings, critical revision of the manuscript for important intellectual content, and approval of the final version. HMM: wrote the initial draft, participated in collecting patient data (pictures and clinical history), reviewing the literature, interpretation of clinical findings, critical revision of the manuscript for important intellectual content, and approval of the final version.\n==== Refs\nREFERENCES\n1 \n\nFischer \nA \n, \nAntoniou \nKM \n, \nBrown \nKK \n, et al. Task force on undifferentiated forms of CTD‐ILD”. An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features\n. Eur Respir J . 2015 ;46 (4 ):976 ‐987\n.26160873 \n2 \n\nPriyangika \nSM \n, \nKarunarathna \nWG \n, \nLiyanage \nI \n, et al. Organizing pneumonia as the first manifestation of anti‐synthetase syndrome\n. BMC Res Notes . 2016 ;2 (9 ):290 .\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "8(8)",
"journal": "Clinical case reports",
"keywords": "Raynaud's; antibodies against cellular antigens; antisynthetase syndrome; interstitial lung disease",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "1586-1587",
"pmc": null,
"pmid": "32884802",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article",
"references": "26160873;27251562",
"title": "A case of antisynthetase syndrome.",
"title_normalized": "a case of antisynthetase syndrome"
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"companynumb": "RO-PFIZER INC-2018333027",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
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"activesubstance": {
"activesubstancename": "CALCIUM"
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{
"abstract": "We describe a case of a 35-year-old woman who presented with bilateral leg weakness and encephalopathy while on long-term valproate therapy. She was diagnosed with valproate-induced encephalopathy due to carnitine deficiency. Clinical improvement occurred with oral carnitine supplementation. Our case report highlights the importance of considering carnitine deficiency in patients presenting with unexplained neurological signs while on long-term valproate treatment.",
"affiliations": "Darlington Memorial Hospital, Darlington, Durham, UK.;Department of Endocrinology and Diabetes, James Cook University Hospital, Middlesbrough, UK.",
"authors": "Al-sharefi|Ahmed|A|;Bilous|Rudy|R|",
"chemical_list": "D018692:Antimanic Agents; D014635:Valproic Acid; D002331:Carnitine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D018692:Antimanic Agents; D001927:Brain Diseases; D009202:Cardiomyopathies; D002331:Carnitine; D005260:Female; D006801:Humans; D022124:Hyperammonemia; D018908:Muscle Weakness; D009135:Muscular Diseases; D011618:Psychotic Disorders; D016896:Treatment Outcome; D014635:Valproic Acid",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26336183",
"pubdate": "2015-09-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17606652;20586533;16277730;23962184;9247410;8740302;20098226;20224318;11581089;22305367;8708702;23451336;16774619;22180549",
"title": "Reversible weakness and encephalopathy while on long-term valproate treatment due to carnitine deficiency.",
"title_normalized": "reversible weakness and encephalopathy while on long term valproate treatment due to carnitine deficiency"
} | [
{
"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-104285",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"d... |
{
"abstract": "BACKGROUND\nPhysicians hospitalize the patients with complicated urinary tract infections (cUTIs) when they need intravenous antibiotics and outpatient parenteral antimicrobial therapy (OPAT) is unavailable. Daily inpatient antimicrobial therapy is an alternative to hospitalization, which is similar to OPAT; patients go home after they are administered antibiotics in a separate room in the hospital setting.\n\n\nOBJECTIVE\nWe assessed our previous daily inpatient practice to revitalize the model in the COVID-19 era.\n\n\nMETHODS\nWe retrospectively evaluated the clinical and microbiological responses and the cost effectiveness of the patients with cUTIs who received daily inpatient ertapenem therapy.\n\n\nRESULTS\nOur study population was 136 patients in 156 episodes. It was a difficult-to-treat group with older age (mean 63.0 ± 14.8 years) and a high burden of underlying conditions (86.5%). The most common causative organisms were Escherichia coli (74.4%) and Klebsiella pneumoniae (19.2%); 89.7% of the isolates were producing extended-spectrum beta lactamase (ESBL). The microbiologic and clinical success rates were 82.1% and 95.5%, respectively. The patients required hospitalization in 16 episodes (10.2%) because of clinical failures (3.8%), superinfections (2%), planned invasive interventions (3.2%), and side effects (1.2%). Our university hospital saved 1608 bed-days and 2596 € (9702 TL) bed costs.\n\n\nCONCLUSIONS\nIn the COVID-19 pandemic period, this seems to be an effective, safe, and cost-effective way to decrease hospitalizations for cUTIs in settings where OPAT is unavailable.",
"affiliations": "Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey.;Infectious Diseases and Clinical Microbiology, Dokuz Eylul Universitesi Tip Fakultesi, Izmir, Turkey.;Infectious Diseases and Clinical Microbiology, Dokuz Eylul Universitesi Tip Fakultesi, Izmir, Turkey.;Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey.;Infectious Diseases and Clinical Microbiology, Dokuz Eylul Universitesi Tip Fakultesi, Izmir, Turkey.;Infectious Diseases and Clinical Microbiology, Dokuz Eylul Universitesi Tip Fakultesi, Izmir, Turkey.;Medical Microbiology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey.",
"authors": "Nazli Zeka|Arzu|A|https://orcid.org/0000-0001-8859-6432;Avkan-Oguz|Vildan|V|;Irmak|Caglar|C|;Eren Kutsoylu|Oya|O|;Alp Cavus|Sema|S|;Kuruüzüm|Ziya|Z|;Ergon|M Cem|MC|",
"chemical_list": "D000900:Anti-Bacterial Agents; D001618:beta-Lactamases; D000077727:Ertapenem",
"country": "England",
"delete": false,
"doi": "10.1111/ijcp.14230",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1368-5031",
"issue": "75(7)",
"journal": "International journal of clinical practice",
"keywords": null,
"medline_ta": "Int J Clin Pract",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D000086382:COVID-19; D000077727:Ertapenem; D004927:Escherichia coli Infections; D006760:Hospitalization; D006801:Humans; D007297:Inpatients; D058873:Pandemics; D012189:Retrospective Studies; D000086402:SARS-CoV-2; D014552:Urinary Tract Infections; D001618:beta-Lactamases",
"nlm_unique_id": "9712381",
"other_id": null,
"pages": "e14230",
"pmc": null,
"pmid": "33864405",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Daily inpatient ertapenem therapy can be an alternative to hospitalization for the treatment of complicated urinary tract infections during the COVID-19 pandemic.",
"title_normalized": "daily inpatient ertapenem therapy can be an alternative to hospitalization for the treatment of complicated urinary tract infections during the covid 19 pandemic"
} | [
{
"companynumb": "TR-009507513-2104TUR006329",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERTAPENEM SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Transarterial hepatic chemoembolization is one of the treatments of unresectable hepatocellular carcinoma in which associated ischemic lesions have been described infrequently. When unusual upper gastrointestinal symptoms or exceeding the so-called post-chemoembolization syndrome after the procedure, the performance of a gastroscopy should be assessed to rule out the occurrence of these complications. The anatomical variants with common origin of gastric and hepatic arteries can favor the migration of the microspheres into gastric territory, forcing the possible modification of the technique to prevent it.",
"affiliations": "Servicio de Aparato Digestivo, Hospital Son Llàtzer. Palma de Mallorca, España.;Servicio de Aparato Digestivo, Hospital Son Llàtzer. Palma de Mallorca, España.;Servicio de Aparato Digestivo, Hospital Son Llàtzer. Palma de Mallorca, España.",
"authors": "de Zárraga Mata|Claudia|C|;Thomás Salom|Guiem|G|;Maura Oliver|Ángela Laura|ÁL|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin",
"country": "Peru",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-5129",
"issue": "39(4)",
"journal": "Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru",
"keywords": null,
"medline_ta": "Rev Gastroenterol Peru",
"mesh_terms": "D000368:Aged; D000903:Antibiotics, Antineoplastic; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D004317:Doxorubicin; D006499:Hepatic Artery; D006801:Humans; D007511:Ischemia; D008113:Liver Neoplasms; D008297:Male; D010437:Peptic Ulcer",
"nlm_unique_id": "9108294",
"other_id": null,
"pages": "367-369",
"pmc": null,
"pmid": "32097399",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ischemic gastroduodenal ulcer as a complication of hepatic hepatocarcinoma transarterial chemoembolization.",
"title_normalized": "ischemic gastroduodenal ulcer as a complication of hepatic hepatocarcinoma transarterial chemoembolization"
} | [
{
"companynumb": "ES-TEVA-2020-ES-1835291",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
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